TECHNICAL FIELD
[0001] The present invention relates to a compound which is a GLP-1 receptor agonist having
the same effect as GLP-1, a salt thereof, or a solvate of either the compound or a
salt of the compound. The present invention further relates to a preventative agent
or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes)
or obesity comprising such a compound, a salt or a solvate as an active ingredient.
BACKGROUND ART
[0002] Glucagon-like peptide-1 (GLP-1) is an incretin secreted from L cells in the small
intestine when nutrients pass through the digestive tract, and it is known that the
GLP-1 demonstrates a wide variety of effects through the GLP-1 receptor, such as promotion
of glucose dependent insulin secretion, inhibition of glucagon secretion, delaying
of gastric emptying, suppression of feeding. Although GLP-1 analog is already commercialized
as a therapeutic agent for diabetes, and seen as one of the most effective therapeutic
agent for diabetes due to its potent effect in HbA1c reduction and weight loss, all
of them require an invasive subcutaneous administration. As such, development of a
GLP-1 receptor agonist that can be non-invasively administered is awaited. Attempts
were made, for example, to improve the bioavailability at the time of oral administration
of a GLP-1 analog: Semaglutide by using an absorbefacient (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate:
SNAC) (Patent Document 1) and to develop a low molecular GLP-1 receptor agonist (Patent
Documents 2 and 3), but a further improvement is required in medicinal properties
including activity, metabolic stability and bioavailability.
[0003] The following two compounds for a chemical library are known as 2-[(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)carbonyl]-1H-indol.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0001)
[0004] Further, Patent Document 4 describes the following pyrazolopyridine derivative as
a compound that is useful in the prevention/therapy of sleeping sickness, leishmaniasis
or the like caused by eukaryote: such as blastocrithidia (e.g. Trypanosomatidae) parasitizing
the patient.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0002)
CITATION LIST
PATENT LITERATURE
SUMMARY OF INVENTION
TECHNICAL PROBLEM
[0006] The problem to be solved by the present invention is to provide a compound which
is a GLP-1 receptor agonist having the same effect as GLP-1 peptide that may be non-invasively
administered and has an improved activity, metabolic stability and bioavailability,
a salt thereof, or a solvate of either the compound or a salt of the compound, and
also to provide a preventative agent or a therapeutic agent for non-insulin-dependent
diabetes mellitus (Type 2 diabetes) or obesity comprising such a compound, salt or
solvate as an active ingredient.
SOLUTION TO PROBLEM
[0007] The present inventors studied extensively to solve this problem and found that a
compound represented by Formula (I), in which the indole ring and the pyrazolopyridine
structure are bound to each other through a substituent, has the same effect as GLP-1
peptide as a GLP-1 receptor agonis, and thus completed the present invention.
[0008] In other words, the following invention is provided as one aspect of the present
invention.
- [1] A compound represented by Formula (I):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0003)
wherein, X is -N= or -CRa=; Ra is selected from a hydrogen atom, a halogen atom, and C1-6 alkyl;
Y is selected from -C(=O)-, -CHR-, and -S(=O)2-; R is a hydrogen atom or C1-6 alkyl;
Q1 is C6-10 aryl or 5 to 10 membered heteroaryl, wherein C6-10 aryl and 5 to 10 membered heteroaryl are optionally substituted with one to five
substituents independently selected from a halogen atom, C1-6 alkyl (wherein C1-6 alkyl is optionally substituted with one or more halogen atoms), and C1-6 alkoxy;
Q2 is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to 12
membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with
one to three substituents independently selected from a halogen atom, C1-6 alkyl (wherein C1-6 alkyl is optionally substituted with one or more halogen atoms), C1-6 alkoxy, and -NRQaRQb, and further, two C1-6 alkyl groups together with a carbon atom to which they are attached may form C3-8 carbocyclic ring; and RQa and RQb are independently selected from a hydrogen atom, C1-6 alkyl, and (C1-6 alkyl)carbonyl;
R1, R2 and R3 are each independently selected from a hydrogen atom and C1-6 alkyl (wherein, C1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom, C1-6 alkoxy, and hydroxy);
R4, R5 and R6 are independently selected from a hydrogen atom, a halogen atom, and C1-6 alkyl;
R7 and R8together with a carbon atom to which they are attached form a C3-8 cycloalkane ring, wherein the C3-8 cycloalkyl thus formed is optionally substituted with one or more C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more hydroxy;
n1 is an integer of 0 to 3; n2 is an integer of 0 to 5;
R9 is selected from a group represented by Formula (IIa), (IIb), (IIc), (IId):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0004)
-CO2R9f, and -C(=O)-NR9gR9h; and R9a, R9b, R9c, R9d, and R9g are each independently selected from a hydrogen atom, C1-6 alkyl (wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom and C1-6 alkoxy), and (C1-6 alkyl)carbonyl, R9e is a hydrogen atom, or C1-6 alkyl that is optionally substituted with one or more halogen atoms, R9f is a hydrogen atom or C1-6 alkyl, R9h is a hydrogen atom, C1-6 alkyl, (C1-6 alkyl)carbonyl, cyano, or -S(=O)n3-R9i; n3 is an integer of 0 to 2, R9i is C1-6 alkyl;
Z1 is selected from a group represented by Formula (IIIa), (IIIb), (IIIc), (IIId), and
(IIIe):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0005)
wherein Rza is selected from a hydrogen atom, C1-6 alkyl, and (C1-6 alkyl)carbonyl, Rzb and Rzc are independently a hydrogen atom or C1-6 alkyl, n4 is an integer of 1 to 3, n5 and n6 are independently an integer of 0 to
10 (* represents a binding position with a pyrazolopyridine structure, ** represents
a binding position with Z2);
Z2 is selected from i) C3-15 cycloalkyl that is optionally substituted with one or more -NRzdRze, ii) C6-10 aryl that is optionally substituted with one to three substituents independently
selected from Group C, and iii) 5 to 10 membered heteroaryl that is optionally substituted
with one to three substituents independently selected from Group D:
Group C:
- a) a halogen atom,
- b) -NRzd2Rze2; wherein Rzd2 and Rze2 are independently selected from a hydrogen atom, C1-6 alkyl and (C1-6 alkyl)carbonyl, wherein C1-6 alkyl is optionally substituted with one or more C1-6 alkoxy,
- c) -S(=O)n7-Rzh1; wherein n7 is an integer of 0 to 2, Rzh1 is C1-6 alkyl,
- d) C1-6 alkyl;
- e) C1-6 alkoxy; wherein C1-6 alkoxy is optionally substituted with one or more hydroxy,
- f) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally
substituted with one or more substituents independently selected from -NRZk1RZl1, wherein Rzk1 and Rzl1 are independently selected from a hydrogen atom and C1-6 alkyl.
Group D:
- a) oxo,
- b) a halogen atom,
- c) C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom, hydroxy, C1-6 alkoxy, and 3 to 12 membered heterocyclyl, wherein 3 to 12 membered heterocyclyl
is optionally substituted with one or more C1-6 alkyl, and
- d) 3 to 12 membered heterocyclyl;;
a salt thereof, or a solvate of either the compound or a salt of the compound.
- [2] The compound according to [1], a salt thereof, or a solvate of either the compound
or a salt of the compound, wherein Q1 is phenyl or pyridyl, and phenyl or pyridyl is substituted with one to four substituents
independently selected from a halogen atom and C1-6 alkyl.
- [3] The compound according to either [1] or [2], a salt thereof, or a solvate of either
the compound or a salt of the compound, wherein Y is -C(=O)-.
- [4] The compound according to any one of [1] to [3], a salt thereof, or a solvate
of either the compound or a salt of the compound, wherein R1 is a hydrogen atom.
- [5] The compound according to any one [1] to [4], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein n1 and n2 are both 0.
- [6] The compound according to any one of [1] to [5], a salt thereof, or a solvate
of either the compound or a salt of the compound, wherein R9 is represented by Formula (IIb):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0006)
- [7] The compound according to any one of [1] to [6], a salt thereof, or a solvate
of either the compound or a salt of the compound, wherein X is -N=, -CH=, or -CF=.
- [8] The compound according to any one of [1] to [7], a salt thereof, or a solvate
of either the compound or a salt of the compound, wherein Z1 is represented by Formula (IIIa):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0007)
(* represents a binding position with a pyrazolopyridine structure, ** represents
a binding position with Z2).
- [9] The compound according to [1], a salt thereof or a solvate of either the compound
or a salt of the compound, which is:
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0008)
- [10] The compound according to [9], a salt thereof, or a solvate of either the compound
or a salt the compound represented by the formula:
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0009)
- [11] The hemicalcium salt hydrate of the compound according to [10].
- [12] A pharmaceutical composition comprising the compound according to any one of
[1] to [11], a salt thereof, or a solvate of either the compound or a salt of the
compound as an active ingredient.
- [13] The compound according to any one of [1] to [11], a salt thereof, or a solvate
of either the compound or a salt of the compound, for use in the prevention or treatment
of non-insulin-dependent diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired
glucose tolerance, insulin dependent diabetes mellitus (Type 1 diabetes), diabetic
complication, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart
disease, brain infarction, non-alcoholic steatohepatitis, Parkinson's disease, or
dementia.
- [14] The compound according to any one of [1] to [11], a salt thereof, or a solvate
of either the compound or a salt of the compound, for use in the prevention or treatment
of non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity.
[0009] Herein disclosed is a preventive agent or a therapeutic agent for non-insulin-dependent
diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin
dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension,
hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic
steatohepatitis, Parkinson's disease, or dementia, wherein the preventative agent
or the therapeutic agent comprises the compound according to any one of [1] to [11],
a salt thereof, or a solvate of either the compound or a salt of the compound as an
active ingredient. An example of dementia is Alzheimer's disease.
[0010] Herein disclosed is a preventive agent or a therapeutic agent for non-insulin-dependent
diabetes mellitus (Type 2 diabetes) or obesity comprising the compound according to
any one of [1] to [11], a salt thereof, or a solvate of either the compound or a salt
of the compound as an active ingredient.
[0011] Herein disclosed is a compound for use in a method for preventing or treating non-insulin-dependent
diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin
dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension,
hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic
steatohepatitis, Parkinson's disease, or dementia, which comprises administering an
effective amount of the compound according to any one of [1] to [11], a salt thereof,
or a solvate of either the compound or a salt of the compound to a subject. An example
of dementia is Alzheimer's disease.
[0012] Herein disclosed is a compound for use in a method for preventing or treating non-insulin-dependent
diabetes mellitus (Type 2 diabetes) or obesity, which comprises administering an effective
amount of the compound according to any one of [1] to [11], a salt thereof, or a solvate
of either the compound or a salt of the compound to a subject.
ADVANTAGEOUS EFFECTS OF INVENTION
[0013] The compound, a salt thereof, or a solvate of either the compound or a salt of the
compound of the present invention is has an effect similar to GLP-1 peptide as a GLP-1
receptor agonist, and provides a non-peptide agent for preventing or treating non-insulin-dependent
diabetes mellitus (Type 2 diabetes) or obesity which is expected to provide a sufficient
bioavailability through oral administration.
BRIEF DESCRIPTION OF DRAWINGS
[0014]
Fig. 1 shows the result of measurement by X-ray powder diffractometry of the crystal
of a sodium salt hydrate of Compound 1 obtained in Example 163 (Sample 160a). The
vertical axis shows the diffraction intensity and the horizontal axis shows the diffraction
angle 2θ (°).
Fig. 2 shows the result of measurement by X-ray powder diffractometry of the crystal
of a sodium salt hydrate of Compound 1 obtained in Example 163 (Sample 160b). The
vertical axis shows the diffraction intensity and the horizontal axis shows the diffraction
angle 2θ (°).
Fig. 3 shows the result of measurement by X-ray powder diffractometry of the crystal
of Example Compound 66 obtained in Example 163 (Sample 161a). The vertical axis shows
the diffraction intensity and the horizontal axis shows the diffraction angle 2θ (°).
Fig. 4 shows the result of measurement by X-ray powder diffractometry of the crystal
of Example Compound 66 obtained in Example 163 (Sample 161b). The vertical axis shows
the diffraction intensity and the horizontal axis shows the diffraction angle 2θ (°).
Fig. 5 shows the result of measurement by X-ray powder diffractometry of the crystal
of a calcium salt hydrate of Example Compound 67 obtained in Example 163 (Sample 162a).
The vertical axis shows the diffraction intensity and the horizontal axis shows the
diffraction angle 2θ (°).
Fig. 6 shows the result of measurement by X-ray powder diffractometry of the crystal
of a calcium salt hydrate of Example Compound 67 obtained in Example 163 (Sample 162b).
The vertical axis shows the diffraction intensity and the horizontal axis shows the
diffraction angle 2θ (°).
Fig. 7 shows the result of thermogravimetry/ differential thermal analysis of the
crystal of a sodium salt hydrate of Compound 1 obtained in Example 164. The horizontal
axis shows temperature (°C), and the right vertical axis shows the weight change (%)
of the sample in thermogravimetry. The left vertical axis shows the heat flow observed
in the differential thermal analysis.
Fig. 8 shows the result of thermogravimetry/ differential thermal analysis of the
crystal of a calcium salt hydrate of Example Compound 67 obtained in Example 164.
The horizontal axis shows temperature (°C), and the right vertical axis shows the
weight change (%) of the sample in thermogravimetry. The left vertical axis shows
the heat flow observed in the differential thermal analysis.
Fig. 9 shows the impact of Example Compound 67 and exenatide against insulin secretion
after intravenous administration of glucose in male cynomolgus monkeys. The area under
the curve of insulin is shown by a mean value ± standard error (n=6). Each pharmaceutical
agent was administered in a crossover design. * indicates that the value of the group
shows a statistically significant difference versus that of vehicle group at P<0.025
, and ** indicates that the value of the group shows a statistically significant difference
versus that of vehicle group at P<0.005 (Williams test). The concentration of each
drug is a mean value of the measured plasma concentration of the drug.
Fig. 10 shows the impact of Example Compound 67 and exenatide against plasma glucose
levels after intravenous administration of glucose in male cynomolgus monkeys. The
area under the curve of plasma glucose is shown by a mean value ± standard error (n=6).
Each pharmaceutical agent was administered in a crossover design. * indicates that
the value of the group shows a statistically significant difference versus that of
vehicle group at P<0.025, and ** indicates that the value of the group shows a statistically
significant difference versus that of vehicle group at P<0.005 (Williams test). The
concentration of each drug is a mean value of the measured plasma concentration of
drug.
Fig. 11 shows the impact of Example Compound 67 and exenatide against the food intake
of male cynomolgus monkeys. The food intake is shown by a mean value ± standard deviation
(n=6). Each pharmaceutical agent was administered in a crossover design. * indicates
that the value of the group shows a statistically significant difference versus that
of vehicle group at P<0.025, and ** indicates that the value of the group shows a
statistically significant difference versus that of vehicle group at P<0.005 (Williams
test).
Fig. 12 shows the time profile of the plasma concentrations for the drug after oral
administration of this substance to male cynomolgus monkeys. Plasma concentrations
are represented by mean values of n=2 for each dosage.
DESCRIPTION OF EMBODIMENTS
[0015] The present invention is further described below.
Definition
[0016] The term "a halogen atom" in the present invention means a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like. A halogen atom that is preferred
as a substituent of aryl in the present invention (e.g. R
a when X in Formula (I) is -CR
a=) is a fluorine atom and a chlorine atom. A halogen atom that is preferred as a substituent
of alkyl in the present invention (e.g. a substituent of C
1-
6 alkyl when the C
6-10 aryl or the 5 to 10 membered heteroaryl of Q
1 is substituted with C
1-6 alkyl) is a fluorine atom and a chlorine atom. Specific examples of C
1-6 alkyl having a halogen atom as a substituent include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl,
4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl,
6-chlorohexyl, and 6,6,6-trifluorohexyl.
[0017] The term "C
1-
6 alkyl" in the present invention is a straight chain or branched chain alkyl group
with 1 to 6 carbons. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl,
1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.
[0018] The term "C
1-6 alkoxy" in the present invention means a group: C
1-
6 alkyl-O- group, of which C
1-
6 alkyl is already defined. Examples include methoxy, ethoxy, n-propoxy, i-propoxy,
n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy,
2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy,
and 2-ethylbutoxy.
[0019] The term "(C
1-
6 alkyl)carbonyl" in the present invention means a group: (C
1-
6 alkyl)-C(O)- group, of which C
1-
6 alkyl is already defined. Examples include methylcarbonyl (acetyl), ethylcarbonyl
(propionyl), n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl,
sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl,
2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, n-hexylcarbonyl,
4-methylpentylcarbonyl, and 2-ethylbutylcarbonyl.
[0020] The term "C
6-10 aryl" in the present invention means an aromatic carbocyclic group, and it may contain
a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic,
or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic
aryl ring. Examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl, isochromanyl,
2,4-dihydro-1H-isoquinolin-3-onyl, and 1,3-dihydrobenzimidazol-2-onyl. A preferable
example is phenyl.
[0021] The term "heteroaryl" in the present invention means an aromatic 5 to 10 membered
cyclic group that comprise, among atoms constituting a ring, one or more hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom, and it may contain
a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic,
or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic
heteroaryl ring. Examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl,
benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl,
benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl,
and benzoisothiazolyl.
[0022] The term "heterocyclyl" in the present invention means a non-aromatic cyclic group
comprising one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms,
and it may be completely saturated or partly unsaturated. The ring may be a monocyclic
ring, a bicyclic ring or a spiro ring of 3 to 12 members, preferably 3 to 10 members.
Examples include oxetanyl, azetidinyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl
, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl,
2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl,
oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl,
indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, and tropanyl.
[0023] The term "C
3-
15 cycloalkyl" of the present invention means a monovalent group derived by removing
any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to
15 carbons. Also, the term "C
3-
8 cycloalkyl" means a cycloalkyl of three to eight carbons. Examples include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Also, the term "C
3-
6 cycloalkyl" means a cycloalkyl of 3 to 6 carbons. When two groups together form a
C
3-
15 cycloalkane ring, the resulting group is bivalent. Examples include cyclopropane-1,1-diyl,
cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,
1-diyl, and cyclooctane-1,1-diyl.
[0024] When the two groups on two carbon atoms are combined to form a C
3-
8 carbocyclic ring, the resulting ring forms a condensed ring. Examples include ring
structures such that the two carbon atoms are linked by -CH
2-, -CH
2CH
2-, -CH
2CH
2CH
2-, -CH
2CH
2CH
2CH
2-, - CH
2CH
2CH
2CH
2CH
2-, and -CH
2CH
2CH
2CH
2CH
2CH
2-.
[0025] In addition, the cycloalkane ring, the carbocyclic ring, the cyclic hydrocarbon in
the cycloalkyl may be a cross-linked ring. Examples of cross-linked rings in the C
3-
15 cycloalkyl include bicyclo[1.1.0]butane, bicyclo[3.2.1]octane, bicyclo[5.2.0]nonane,
bicyclo[4.3.2]undecane, tricyclo[2.2.1.0
2,6]heptane, tricyclo[4.3.1.1
2,5]undecane, tricyclo[3.3.1.1
3,7]decane (adamantane), tricyclo[3.3.1.1
3,7]decane-2-ylidene (2-adamantylidene), pentacyclo[4.2.0.0
2,5.0
3,8.0
4,7]octane (cubane), and examples of C
3-
15 cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl,
bicyclo[4.3.2]undecyl, tricyclo[2.2.1.0
2,6]heptyl, tricyclo[4.3.1.1
2,5]undecyl, adamantyl, 2-adamantylidenyl, and cubanyl.
[0026] The present invention provides a compound represented by Formula (I), a salt thereof,
or a solvate of either the compound or a salt of the compound.
X is -N= or -CRa=; Ra is selected from a hydrogen atom, a halogen atom, and C1-6 alkyl. X is preferably -N=, -CH=, or -CF=, more preferably -CH=.
Y is selected from -C(=O)-, -CHR-, and -S(=O)2-; R is a hydrogen atom or C1-6 alkyl.
Q1 is C6-10 aryl or 5 to 10 membered heteroaryl, wherein C6-10 aryl and 5 to 10 membered heteroaryl are optionally substituted with one to five
substituents independently selected from a halogen atom, C1-6 alkyl (wherein C1-6 alkyl is optionally substituted with one or more halogen atoms), and C1-6 alkoxy. Q1 is preferably phenyl or pyridyl, wherein phenyl or pyridyl is substituted with one
to four substituents independently selected from a halogen atom and C1-6 alkyl. More preferably Q1 is phenyl substituted with two to three substituents independently selected from
a halogen atom and C1-6 alkyl.
[0027] Q
2 is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to 12
membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with
one to three substituents independently selected from a halogen atom, C
1-6 alkyl (wherein C
1-6 alkyl is optionally substituted with one or more halogen atoms), C
1-6 alkoxy, and -NR
QaR
Qb, and two C
1-6 alkyl groups together with a carbon atom to which they are attached may form C
3-8 carbocyclic ring; and R
Qa and R
Qb are independently selected from a hydrogen atom, C
1-6 alkyl, and (C
1-6 alkyl)carbonyl. Preferably, Q
2 is i) 6 membered heterocyclyl, wherein 6 membered heterocyclyl is optionally substituted
with one or more C
1-6 alkyl, and two C
1-6 alkyl groups together with a carbon atom to which they are attached may form C
3-8 carbocyclic ring, or ii) 5 to 6 membered heteroaryl, wherein 5 to 6 membered heteroaryl
is optionally substituted with one to three substituents independently selected from
a halogen atom, C
1-6 alkyl, C
1-6 alkoxy, and -NR
QcR
Qd, and R
Qc and R
Qd are independently selected from a hydrogen atom and C
1-6 alkyl. Preferably, Q
2 is 5 to 6 membered heterocyclyl or heteroaryl, wherein the 5 to 6 membered heterocyclyl
and 5 to 6 membered heteroaryl are optionally substituted with one to three C
1-6 alkyl.
[0028] R
1, R
2 and R
3 are each independently selected from a hydrogen atom and C
1-6 alkyl (wherein, C
1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom, C
1-6 alkoxy, and hydroxy). Preferably, the combination of R
1, R
2 and R
3 is selected from: all hydrogen atoms; R
1is a hydrogen atom, R
2 is a hydrogen atom, and R
3 is C
1-6 alkyl; and R
1 is a hydrogen atom, R
2 is C
1-6 alkyl, and R
3 is C
1-6 alkyl.
[0029] R
4, R
5 and R
6 are independently selected from a hydrogen atom, a halogen atom, and C
1-6 alkyl. It is preferred that R
4, R
5 and R
6 are independently a hydrogen atom or a fluorine atom. More preferably, the combination
of R
4, R
5, and R
6 are: all hydrogen atoms; or R
4 is a hydrogen atom, R
5 is a hydrogen atom, and R
6 is a fluorine atom.
[0030] R
7 and R
8 together with a carbon atom to which they are attached form C
3-8 cycloalkane ring, wherein the C
3-8 cycloalkyl thus formed is optionally substituted with one or more C
1-6 alkyl, wherein C
1-6 alkyl is optionally substituted with one or more hydroxy. The C
3-8 cycloalkyl is preferably C
3-6 cycloalkyl. A preferable C
3-6 cycloalkyl is, for example, cyclopentyl.
[0031] n1 is an integer of 0 to 3; n2 is an integer of 0 to 5. n1 and n2 are each preferably
0 to 2, more preferably 0 to 1, and even more preferably 0. Also, the combination
of n1 and n2 is preferably 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, 2 and 0, more
preferably 0 and 0, 0 and 1, 1 and 0, 2 and 0, and even more preferably 0 and 0.
[0032] R
9 is selected from a group represented by Formula (IIa), (IIb), (IIc), (IId):
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0011)
-CO
2R
9f, and -C(=O)-NR
9gR
9h; and R
9a, R
9b, R
9c, R
9d, and R
9g are each independently selected from a hydrogen atom, C
1-6 alkyl (wherein C
1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom and C
1-6 alkoxy), and (C
1-6 alkyl)carbonyl, R
9e is a hydrogen atom, or C
1-6 alkyl that is optionally substituted with one or more substituents independently
selected from a halogen atom, R
9f is a hydrogen atom or C
1-6 alkyl, R
9h is a hydrogen atom, C
1-6 alkyl, (C
1-6 alkyl)carbonyl, cyano, or -S(=O)
n3-R
9i; n3 is an integer of 0 to 2, and R
9i is C
1-6 alkyl.
[0033] Z
1 is selected from a group represented by Formula (IIIa), (IIIb), (IIIc), (IIId), and
(IIIe) :
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0012)
wherein R
za is selected from a hydrogen atom, C
1-6 alkyl, and (C
1-6 alkyl)carbonyl, R
zb and R
zc are independently a hydrogen atom or C
1-6 alkyl, n4 is an integer of 1 to 3, n5 and n6 are independently an integer of 0 to
10.
* represents a binding position with a pyrazolopyridine structure, ** represents a
binding position with Z2.
Z2 is selected from i) C3-15 cycloalkyl that is optionally substituted with one or more -NRzdRze, ii) C6-10 aryl that is optionally substituted with one to three substituents independently
selected from Group C, and iii) 5 to 10 membered heteroaryl that is optionally substituted
with one to three substituents independently selected from Group D.
[0034] More preferably, Z
2 is selected from i) C
6-10 aryl that is optionally substituted with one to three substituents independently
selected from Group C, and ii) 5 to 10 membered heteroaryl that is optionally substituted
with one to three substituents independently selected from Group D.
[0035] Group C:
- a) a halogen atom,
- b) -NRzd2Rze2; wherein Rzd2 and Rze2 are independently selected from a hydrogen atom, C1-6 alkyl and (C1-6 alkyl)carbonyl, wherein C1-6 alkyl is optionally substituted with one or more C1-6 alkoxy,
- c) -S(=O)n7-Rzh1; wherein n7 is an integer of 0 to 2, Rzh1 is C1-6 alkyl,
- d) C1-6 alkyl;
- e) C1-6 alkoxy; wherein C1-6 alkoxy is optionally substituted with one or more hydroxy,
- f) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally
substituted with one or more substituents independently selected from - NRzk1Rzl1, wherein Rzk1 and Rzl1 are independently selected from a hydrogen atom and C1-6 alkyl.
[0036] Group D:
- a) oxo,
- b) a halogen atom,
- c) C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected
from a halogen atom, hydroxy, C1-6 alkoxy, and 3 to 12 membered heterocyclyl, wherein 3 to 12 membered heterocyclyl
is optionally substituted with one or more C1-6 alkyl, and
- d) 3 to 12 membered heterocyclyl.
[0037] The compound represented by Formula (I) of the present invention is preferably such
that Z
1 is a group represented by Formula (IIIa), Y is -C(=O)-, R
9 is a group represented by Formula (IIb), R
9b is a hydrogen atom, R
7 and R
8 together with a carbon atom to which they are attached form C
3-15 cycloalkane ring that is substituted with one to three C
1-6 alkyl, and the one to three C
1-6 alkyl is unsubstituted.
[0038] Next, examples of the production method of a compound represented by Formula (I),
a salt thereof, or a solvate of either the compound or a salt of the compound are
explained by the following schemes.
[0039] The compound represented by Formula (I), a salt thereof, or a solvate of either the
compound or a salt of the compound are produced by conducting i) General production
method A1 or General production method A2, ii) General production method B, and iii)
General production method C. This production method is one example of a preferable
production method of a compound of Formula (I), in which Z
1 is a group represented by Formula (IIIa), Y is represented by -C(=O)-, R
9 is a group represented by Formula (IIb), and R
9b is a hydrogen atom, that is, a compound represented by Formula (Ia). It is also an
example of a preferable production method for a compound in which R
7 and R
8 together with a carbon atom to which they are attached form a C
3-15 cycloalkane ring substituted with 1 to 3 C
1-6 alkyl groups, wherein the alkyl groups are not substituted. Note that in a case in
which a starting material or a target product of a given step undergoes an undesirable
chemical transformation under the reaction condition of that step, it is possible
to obtain the target product of that step by protecting or deprotecting a functional
group. T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, Fourth Edition,
John Wiley&Sons, Inc., New York (2007) may be referred to in order to select the protecting
group and the method of protection and deprotection. Some examples of the protection
and deprotection of a functional group are shown in the scheme below.
<General production method A1>
[0040] Compound f may be synthesized by the General production method A1 illustrated by
the following scheme.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0013)
wherein, P
2 is a hydrogen atom or C
1-6 alkyl, P
1a is a protective group of amino, P
3a and P
3b are independently C
1-6 alkyl, or P
3a and P
3b together with oxygen atoms to which they are attached and a carbon atom to which
the oxygen atoms are attached may form 5 to 7 membered 1,3-dioxacycloalkane ring,
Y
1 is cyano or -CO-OP
2, Y
2 is =O or =NH, and X
1 is a leaving group.
[0041] A protective group of amino includes for example formyl, (C
1-6 alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
etc.), carbamoyl, C
1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl,
t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl,
9-fluorenylmethyloxycarbonyl, etc.), allyl, and aralkyl. The leaving group includes,
for example, a halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.
Step A1-1a:
[0042] Compound a1 may be obtained by reacting Compound a with a base.
[0043] Examples of the base include metal hydrides such as sodium hydride, potassium hydride,
lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide,
lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide.
A metal alkoxide such as potassium t-butoxide is preferred.
[0044] Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, and dioxane, and THF is preferred.
[0045] The reaction temperature is normally -30°C to 30°C, preferably -10°C to 10°C. The
reaction time is normally 15 min. to 5 h., preferably 30 min. to 3h.
[0046] Compound a1 may be isolated, or it may be subjected to step A1-1b without being isolated.
[0048] Note that Compound a1 may be obtained as an alkali metal salt such as a potassium
salt by being brought into contact with a base used in the reaction, and such salt
may be subjected to the next step.
Step A1-1b:
[0049] Compound a1 may be reacted with Compound a2 to obtain Compound b. This reaction may
preferably be performed in the presence of an acid.
[0050] Examples of the acid include, for example, acids such as hydrochloric acid, acetic
acid, methanesulfonic acid, p-toluenesulfonic acid, and salts of a weak base and a
strong acid such as pyridine-hydrochloric acid salt.
[0051] Examples of the solvent include hydrocarbon-based solvents (hexane, heptane, benzene,
toluene, xylene, etc.) and alcohol-based solvents (methanol, ethanol, etc.).
[0052] Further, water may exist in the reaction mixture.
[0053] The reaction temperature is normally 40°C to 200°C, preferably 60°C to 150°C.
[0054] The reaction time is normally 6 min. to 30 h., preferably 30 min. to 3 h.
[0055] Compound a2 may be commercially obtained as a salt with hydrogen chloride attached
to it from Alfa Aesar, etc. By referring to
Synlett, 2011, 17, 2555-2558, Compound a2 whose hydrazine portion is protected with t-butoxycarbonyl may be put
to use after it is deprotected with an acid such as methanesulfonic acid. Also, by
referring to
Journal of Medicinal Chemistry 2003, 46, 1546-1553, Compound a2 may be synthesized by using compound: Q
1-NH
2 as the starting compound.
Step A1-2:
[0056] Compound b may be reacted with Compound b1 or Compound b2 in the presence of a base
to obtain Compound c.
[0057] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine,
dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine, etc.), metal
hydrides such as sodium hydride, potassium hydride, lithium hydride; and metal alkoxides
such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide,
sodium t-pentoxide, and lithium t-pentoxide. When using Compound b2, a metal alkoxide
such as potassium t-butoxide is preferred.
[0058] Examples of solvents that may be used include alcohol-based solvents such as methanol,
and ethanol; ether-based solvents such as THF, and diethyl ether; ester-based solvents
such as ethyl acetate, and methyl acetate; nitrile-based solvents such as acetonitrile,
benzonitrile, and benzyl cyanide; amide-based solvents such as N,N-dimethyl acetamide
(DMA), N,N-dimethylimidazolidinone (DMI), and DMF. An amide-based solvent such as
DMA is preferred.
[0059] The reaction temperature is normally -50°C to 70°C, preferably -30°C to 50°C.
[0060] The reaction time is normally 15 min. to 72 h., preferably 1 h. to 30 h.
[0061] Compound b1 may be commercially obtained from Enamine LTD., etc. By referring to
WO 2006/048727, Compound b1 may be synthesized by reacting compound: H
2NCH
2CH(OP
3a)(OP
3b) and phosgene or triphosgene. Compound b2 may be commercially obtained from UkrOrgSyntez
Ltd., etc. By referring to
WO 99/50262, Compound b2 may be synthesized by reacting compound: H
2NCH
2CH(OP
3a)(OP
3b) and diisocyanate such as CDI
Step A1-3:
[0062] Compound c may be reacted with an acid to obtain Compound d.
[0063] Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid (formic
acid (FA), acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic
acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic
acid, fluoroacetic acid, trifluoroacetic acid (TFA), tartaric acid, propionic acid,
glutaric acid, etc.).
[0064] Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based
solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents
(N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone), alcohol-based
solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol,
sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol,
ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate
ester-based solvents (methyl acetate, ethyl acetate, isopropyl acetate), acetonitrile,
and a mixed solvent thereof. An ether-based solvent such as tetrahydrofuran is preferred.
[0065] The reaction temperature is normally 0°C to 100°C, preferably 10°C to 80°C.
[0066] The reaction time is normally 10 min. to 20h., preferably 30 min. to 5 h.
Step A1-4:
[0067]
- a) When Z2 is C1-6 alkyl, C3-15 cycloalkyl and 3 to 12 membered heterocyclyl, Compound d may be reacted with Compound
d1 in the presence of a base to obtain Compound e.
[0068] Examples of the base include metal hydrides such as sodium hydride, potassium hydride,
and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-butoxide,
lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide;
and metal alkyls such as butyllithium, and ethyllithium.
[0069] Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based
solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), and amide-based solvents
(N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, etc.). An amide-based
solvent such as N,N-dimethyl acetamide is preferred.
[0070] The reaction temperature is normally 0°C to 150°C, preferably 20°C to 120°C.
[0071] The reaction time is normally 15 min. to 24h., preferably 30 min. to 5 h.
[0072] b) When Z
2 is C
6-10 aryl and 5 to 10 membered heteroaryl, Compound d may be reacted with Compound d1
in the presence of a base, a copper catalyst and a ligand, to obtain Compound e.
[0073] Examples of the base include a weak basic inorganic salt (sodium carbonate, potassium
carbonate, potassium phosphate, cesium carbonate, etc.), and organic base (triethyl
amine, pyridine, tetrabutylammonium fluoride, etc.). A weak basic inorganic salt such
as potassium carbonate is preferred.
[0074] Examples of the copper catalyst include copper iodide (I), copper bromide (I), copper
chloride (I), copper acetate (I), copper oxide (II), and copper trifluoromethanesulfonate
(I), and copper iodide (I) is preferred.
[0075] Examples of the ligand include phenanthroline, quinolin-8-ol, 2,2,6,6-tetramethylheptane-3,5-dione,
and diamines such as N,N'-dimethylethane-1,2-diamine, trans-cyclohexane-1,2-diamine,
and trans-N,N'-dimethylcyclohexane-1,2-diamine, and trans-N,N'-dimethylcyclohexane-1,2-diamine
is preferred.
[0076] Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-based
solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents
(N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, etc.), alcohol-based
solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol,
sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol,
ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate
ester-based solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), and
acetonitrile, and an amide-based solvent such as N-methylpyrrolidone is preferred.
[0077] The reaction temperature is normally 30°C to 200°C, preferably 60°C to 160°C.
[0078] The reaction time is normally 1 h. to 15 h., preferably 3 h. to 9 h.
Step A1-5:
[0079] Compound e may be deprotected to obtain Compound f.
[0080] When the protective group P
1a is C
1-6 alkoxycarbonyl such as t-butoxycarbonyl, it is preferable to use an acid for deprotection.
[0081] Examples of the acid include inorganic acid (hydrogen chloride, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic
acid, benzenesulfonic acid, toluene sulfonic acid, etc.), and carboxylic acid (formic
acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,
succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic
acid, fluoroacetic acid , trifluoroacetic acid, tartaric acid, propionic acid, glutaric
acid, etc.).
[0082] Examples of the solvent include ether-based solvents (tetrahydrofuran, methyltetrahydrofuran,
diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane,
etc.), hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.), amide-based
solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, etc.),
and halogen-based solvents (dichloromethane, chloroform, carbon tetrachloride, etc.),
and an amide-based solvent such as N-methylpyrrolidone is preferred.
[0083] The reaction temperature is normally 0°C to 200°C, preferably 10°C to 120°C.
[0084] The reaction time is normally 30 min. to 10 h., preferably 1 h. to 6 h.
[0085] Note that Compound f may be obtained as a salt with the acid used in the reaction,
and such salt may be subjected to the next step.
<General production method A2>
[0086] When Z
2 is a bulky group such as C
3-15 cycloalkyl that is substituted with -NR
zdR
ze, it is possible to synthesize Compound p corresponding to Compound f by General production
method A2 as illustrated by the following scheme.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0014)
[0087] In the formulae, Z
2a is non-substituted C
3-15 cycloalkyl or 3 to 12 membered heterocyclyl.
[0088] P
1a and P
2a are protective groups of amino,
X2, X3, X4 and X5 are each independently a leaving group,
R10a and R10b are independently C1-6 alkyl, or R10a and R10b together with oxygen atoms to which they are attached and a carbon atom to which
the oxgen atoms are attached may form a 5 to 7 membered 1,3-dioxacycloalkane ring.
[0089] Examples of the protective group of amino include formyl, (C
1-6 alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
etc.), carbamoyl, C
1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-butoxycarbonyl,
t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl,
9-fluorenylmethyloxycarbonyl, etc.), allyl, aralkyl.
[0090] Examples of the leaving group include a halogen atom, acetyloxy, trifluoroacetyloxy,
methanesulfonyloxy, and paratoluenesulfonyloxy.
Step A2-1:
[0091] Compound g may be reacted with an azide in the presence of a base, to obtain Compound
h.
[0092] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.).
[0093] Examples of the azide include metal azides such as sodium azide, trimethylsilyl azide,
and diphenylphosphoryl azide, and diphenylphosphoryl azide is preferred.
[0094] Examples of the solvent include ether-based solvents (tetrahydrofuran, methyltetrahydrofuran,
diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane,
etc.), hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.), and amide-based
solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone), and
a hydrocarbon-based solvent such as toluene is preferred.
[0095] The reaction temperature is normally 0°C to 150°C, preferably 10°C to 100°C.
[0096] The reaction time is normally 1 h. to 10 h., preferably 2 h. to 6 h.
Step A2-2:
[0098] Compound b obtained in Step A1-1b may be reacted with Compound h in the presence
of a base, to obtain Compound i.
[0099] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine,
etc.).
[0100] Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, dioxane; and hydrocarbon-based solvents such as hexane, heptane, benzene,
toluene, etc. A base such as pyridine may also be used as the solvent.
[0101] The reaction temperature is normally 0°C to 60°C, preferably 5°C to 45°C.
[0102] The reaction time is normally 30 min. to 50 h., preferably 2 h. to 10 h.
Step A2-3:
[0103] Compound i may be reacted with Compound i1 or Compound i2 in the presence of a base
to obtain Compound j.
[0104] The base includes a weak basic inorganic salt (sodium carbonate, potassium carbonate,
cesium carbonate, etc.), and metal hydrides (sodium hydride, potassium hydride, etc.),
and a weak basic inorganic salt such as cesium carbonate is preferred.
[0105] Examples of Compound i1 include 1,2-dichloro-1-methoxyethane, 1,2-dichloro-1-ethoxyethane,
and 1,2-dichloro-1-i-propoxyethane, and 1,2-dichloro-1-t-butoxyethane, and 1,2-dichloro-1-ethoxyethane
is preferred. Compound i1 may be commercially obtained from Tokyo Chemical Industry
Co., Ltd. or FCH Group.
[0106] Examples of Compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane,
2-bromo-1,1-dimethoxyethane, and 2-bromo-1,1-ethoxyethane. Compound i2 may be commercially
obtained from Tokyo Chemical Industry Co., Ltd.
[0107] Examples of the solvent include alcohol-based solvents such as methanol, ethanol;
ether-based solvents such as THF, diethyl ether; ester-based solvents such as ethyl
acetate, methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile,
benzyl cyanide; and amide-based solvents such as N,N-dimethyl acetamide (DMA), N,N-dimethyl
imidazolidinone (DMI), DMF. An amide-based solvent such as DMA is preferred.
[0108] The reaction temperature is normally 0°C to 60°C, preferably 20°C to 45°C.
[0109] The reaction time is normally 1 h. to 72 h., preferably 12 min. to 35 h.
Step A2-4:
[0110] Compound j may be reacted with acid to obtain Compound k.
[0111] Examples of the acid include an inorganic acid (hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), a sulfonic acid (methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and a carboxylic acid (formic
acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,
succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic
acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric
acid, etc.), and a sulfonic acid such as methanesulfonic acid is preferred.
[0112] Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, and dioxane, and THF is preferred.
[0113] The reaction temperature is normally 0°C to 100°C, preferably 20°C to 80°C.
[0114] The reaction time is normally 15 min. to 6 h., preferably 30 min. to 3 h.
Step A2-5:
[0115] Compound k may be reacted with Compound k1 in the presence of a base, to obtain Compound
1.
[0116] Examples of Compound k1 include C
1-6 alkyl halides such as methyl iodide, and (C
1-6 alkyl)carbonyl halides such as acetyl chloride. When R
zd is (C
1-6 alkyl)carbonyl, it is preferred to use an acid anhydride that is represented as ((C
1-
6 alkyl)carbonyl)
2O, for example, an acetic anhydride in place of Compound k1.
[0117] Examples of the base include metal hydrides such as sodium hydride, potassium hydride,
and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide,
lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-pentoxide.
A metal alkoxide such as potassium pentoxide is preferred.
[0118] Examples of the solvent includes ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, dioxane; and hydrocarbon-based solvents such as hexane, heptane, benzene,
toluene. THF is preferred.
[0119] The reaction temperature is normally -50°C to 50°C, preferably -40°C to 40°C.
[0120] The reaction time is normally 1 min. to 2 h., preferably 3 min. to 30 min.
Step A2-6:
[0121] Compound 1 may be deprotected to obtain Compound m.
[0122] An appropriate reagent or reaction condition may be selected according to the type
of the protective group in deprotection. When the protective group is t-butoxycarbonyl,
a reaction with an acid is preferred.
[0123] Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid (formic
acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid,
succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic
acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric
acid, etc.), and carboxylic acid such as trifluoroacetic acid is preferred.
[0124] Examples of the solvent include ether-based solvents such as diethyl ether, THF,
dimethoxyethane, etc.; halogen-based solvents such as dichloromethane (CH
2Cl
2), chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. A halogen-based
solvent such as CH
2Cl
2 is preferred.
[0125] The reaction temperature is normally 0°C to 60°C, preferably 10°C to 40°C.
[0126] The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.
[0127] Note that Compound m may be obtained as a salt with the acid used in the reaction,
and such salt may be subjected to Step A2-7.
Step A2-7:
[0128] An amino in Compound m may be protected to obtain Compound n.
[0129] An appropriate reagent or reaction condition may be selected according to the type
of protective group in protection. When the protective group is C
1-6 alkoxycarbonyl, a reaction with a base is preferred.
[0130] Examples of the compound used for protection include methoxycarbonyl chloride, ethoxycarbonyl
chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9-fluorenylmethyloxycarbonyl
chloride (Fmoc-Cl), and di-t-butyl dicarbonate, and di-t-butyl dicarbonate is preferred.
[0131] Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine,
etc.), and a tertiary amine such as triethyl amine is preferred.
[0132] Examples of the solvent includes ether-based solvents such as diethyl ether, THF,
dimethoxyethane, etc.; halogen-based solvents such as dichloromethane (CH
2Cl
2), chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. A halogen-based
solvent such as CH
2Cl
2 is preferred.
[0133] The reaction temperature is normally 0°C to 60°C, preferably 15°C to 40°C.
[0134] The reaction time is normally 30 min. to 20 h., preferably 1 h. to 5 h.
Step A2-8:
[0135] Compound n may be reacted with Compound n1 in the presence of a base to obtain Compound
o.
[0136] Examples of Compound n1 include C
1-6 alkyl halides such as methyl iodide, and (C
1-6 alkyl)carbonyl halide such as acetyl chloride. When R
ze is C
1-6 alkyl, it is preferred that C
1-6 alkyl is either not substituted or substituted with C
1-6 alkoxy.
[0137] This step is performed similarly to Step A2-5, and the base, and solvent used in
the reaction, and reaction temperature, reaction time are similar to Step A2-5.
Step A2-9:
[0138] Compound o may be deprotected to obtain Compound p.
[0139] An appropriate reagent or reaction condition may be selected according to the type
of protective group in deprotection. When the protective group P
1a is C
1-6 alkoxycarbonyl such as t-butoxycarbonyl, deprotection using an acid is preferred.
[0140] This step is performed similarly to Step A1-5, and the acid, and solvent used in
the reaction, and reaction temperature, reaction time are similar to Step A1-5.
<General production method B>
[0141] It is possible to synthesize Compound bf by General production method B as illustrated
by the following scheme.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0015)
[0142] In the formulae, P
21 is hydroxy, C
1-6 alkoxy, or -NR
21aR
21b, and R
21a and R
21b are independently a hydrogen atom, C
1-6 alkyl or C
6-10 aryl,
X21 is a hydrogen atom, a halogen atom, or -Zn-X21a,
X21a is a bromine atom or an iodine atom, and
X22 is a leaving group.
[0143] The leaving group includes, for example, a halogen atom, acetyloxy, trifluoroacetyloxy,
methanesulfonyloxy, paratoluenesulfonyloxy.
Step B-1:
[0144] Compound ba may be reacted with Compound ba1 in the presence of a palladium catalyst
to obtain Compound bb.
[0145] The complex formed in the reaction mixture by separately adding a palladium compound
and a ligand may be used as the palladium catalyst. The complex that has been prepared
separately may be used. Examples of the ligand include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,
trimethylenebis(diphenylphosphine), 2-(di-t-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl,
2-(di-t-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl.
Examples of palladium compounds that may be combined with a ligand include, for example,
di-µ-chlorobis[(η-allyl)palladium(II)], tetrakis(triphenylphosphine)palladium(0).
[0146] Examples of the palladium catalyst that may be used with the present step include
tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphine
Cobalt(II), palladium(II) acetate, bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct,
dichlorobis(triphenylphosphine)palladium(II), palladium hydroxide, tetrakis(triphenylphosphine)palladium(0),
and di-µ-chlorobis[(η-allyl)palladium(II)]. It is preferred to use a complex formed
from a palladium compound of di-µ-chlorobis[(η-allyl)palladium(II)] and a ligand of
2-(di-t-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl as a catalyst in Step
11.
[0147] Note that the step may be performed in the presence of a base.
[0148] Examples of the base includes a weak basic inorganic salt (sodium carbonate, potassium
carbonate, cesium carbonate, sodium acetate, potassium acetate, calcium acetate, etc.),
metal hydrides (sodium hydride, potassium hydride, etc.), and metal alkoxides (potassium
t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide,
lithium t-pentoxide, etc.).
[0149] Examples of the reaction solvent include ether-based solvents such as tetrahydrofuran
(THF), diethyl ether, dioxane, etc.; amide-based solvents such as N,N-dimethyl acetamide
(DMA), N,N-dimethylimidazolidinone (DMI), DMF. The solvent may be a mixture with water.
[0150] The reaction temperature is normally 10°C to 200°C, preferably 40°C to 130°C.
[0151] The reaction time is normally 1 min. to 20 h., preferably 10 min. to 10 h.
[0152] Compound ba may be obtained commercially from Aurora Fine Chemicals. It may also
be synthesized by referring to
Synthetic Communications, 39(14), 2506-2515, 2009. It may also be obtained by esterifying or amidating Compound ba in which -COP
21 is -COOH. Compound ba1 whose X
21 is -Zn-X
21a may be obtained commercially from Focus Synthesis LLC. It may be synthesized by referring
to
WO 2014/201206.
Step B-2:
[0153] Compound bb may be reacted with Compound bb1 in the presence of a base to obtain
Compound be.
[0154] Examples of the base include metal hydrides such as sodium hydride, potassium hydride,
etc., and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, and cesium hydroxide, and potassium hydroxide is preferred.
[0155] Examples of the reaction solvent include amide-based solvents such as N,N-dimethyl
acetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, and DMI is preferred.
The solvent may be a mixture with water.
[0156] The reaction temperature is normally -10°C to 100°C, preferably 0°C to 45°C.
[0157] The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.
Step B-3:
[0159] Compound be may be reacted with hydroxyamine (H
2NOH) to obtain Compound bd.
[0160] Examples of the reaction solvent include aprotic polar solvents such as dimethylsulfoxide
(DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, and alcohol-based
solvents such as methanol and ethanol, and DMSO is preferred. The solvent may be a
mixture with water.
[0161] The reaction temperature is normally -10°C to 100°C, preferably 20°C to 45°C.
[0162] The reaction time is normally 2 h. to 72 h., preferably 3 h. to 36 h.
[0163] Compound bd may be subjected to Step B-4 without being isolated or purified.
Step B-4:
[0164] Compound bd may be reacted with triphosgene, chloro-carbonic acid ester (methyl chlorocarbonate,
ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), carbonyl diimidazole, etc.,
preferably carbonyl diimidazole in the presence of a base, to obtain Compound be.
[0165] Examples of the base include tertiary amines (triethyl amine, N-methylmorpholine,
diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), DABCO, etc.), and metal
hydroxides (sodium hydroxide, potassium hydroxide), and a tertiary amine such as DBU
is preferred.
[0166] Examples of the solvent include aprotic polar solvents such as dimethylsulfoxide
(DMSO), dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, alcohol-based
solvents such as methanol and ethanol, and ether-based solvents such as tetrahydrofuran
(THF), diethyl ether, and dioxane, and DMSO is preferred.
[0167] The reaction temperature is normally -10°C to 100°C, preferably 20°C to 45°C.
[0168] The reaction time is normally 10 min. to 10 h., preferably 15 min. to 2 h.
Step B-5:
[0169] Compound be that is protected with P
21 may be deprotected using a base to obtain Compound bf.
[0170] Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium
hydroxide, potassium hydroxide, and cesium hydroxide; and metal alkoxides such as
potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide,
sodium t-pentoxide, and lithium t-pentoxide.
[0171] Examples of the solvent include alcohol-based solvents such as methanol, ethanol,
methoxy ethanol, t-butylalcohol; ether-based solvents such as THF, diethyl ether;
and amide-based solvents such as N,N-dimethyl acetamide (DMA), N,N-dimethylimidazolidinone
(DMI), and DMF. The solvent may also be a mixture with water.
[0172] The reaction temperature is normally -20°C to 120°C, preferably 20°C to 100°C.
[0173] The reaction time is normally 20 min. to 10 h., preferably 30 min. to 5 h.
[0174] Note that the order of Steps B-1, B-2, B-3, B-4 and B-5 may be changed. For example,
Compound ba may be sequentially subjected to Step B-2, and Step B-1 to obtain Compound
be. Compound ba may be sequentially subjected to Step B-2, Step B-3, Step B-4, Step
B-5, and Step B-1 to obtain Compound bf. Compound ba may be sequentially subjected
to Step B-2, Step B-3, Step B-4, Step B-1 and Step B-5 to obtain Compound bf.
Step B-Aa and Step B-Ab:
[0175] Further when X
21 is a halogen atom, Compound ba may be subjected to the following Step B-Aa and Step
B-Ab to obtain Compound bb, and Compound bb may also be subjected to Step B-2.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0016)
[0176] In the formulae, R
Qc and R
Qd are independently a hydrogen atom or C
1-6 alkyl, or R
Qc and R
Qd together with oxygen atoms to which they are attached and a carbon atom to which
the oxygen atoms are attached may form 1,3,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.
Step B-Aa:
[0177] Compound ba may be reacted with Compound ba2 or Compound Ba3 in the presence of a
palladium catalyst to obtain an organic boron Compound baa. This step may be performed
in the presence of a base.
[0178] This step is performed similarly to Step B-1, and the palladium catalyst, the base,
the solvent used in the reaction, or the reaction temperature, reaction time are similar
to Step B-1.
[0179] Examples of Compound ba2 include pinacol borane, 4,6,6-trimethyl-1,3,2-dioxaborinane.
Compound ba3 includes, for example, diboronic acid, pinacol diborane(4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)),
bis(neopentyl glycolato)diboron, and bis(hexylene glycolato)diboron. These compounds
may be obtained as a commercial product from
Tokyo Chemical Industry Co., Ltd. By referring to Journal of the American Chemical
Society, 131(45), 16346-16347, 2009 or
Organic Synthesis, 77, 176-185, 2000, they may also be synthesized using i) pinacol and ii) diborane, BH
3 • THF complex or BH
3 • dimethyl sulfide complex.
[0180] The organic boron compound baa may be subjected to Step B-Ab without being isolated.
Step B-Ab:
[0181] An organic boron compound baa may be reacted with Compound ba1 in the presence of
base to obtain Compound bb.
[0182] Examples of the base include a weak basic inorganic salt (sodium carbonate, potassium
carbonate, cesium carbonate, sodium acid carbonate, potassium acid carbonate, etc.),
and sodium carbonate is preferred.
[0183] The solvent used in the reaction or the reaction temperature, reaction time is the
same as Step B-1.
[0184] Note that a transformation of Compound ba1 to an organic boron compound similar to
the transformation of Compound ba to Compound baa, followed by a reaction thereof
with Compound ba also provides Compound bb.
Step B-B:
[0185] Further, when Compound bb1 is represented by X
21-(CH
2)
n1-CH
2-CN, Compound bca corresponding to Compound be obtained in Step B-2 may be subjected
to Step B-B, that is, reacted with Compound bc1 in the presence of a base to give
Compound bcb corresponding to Compound bc, in which R
7 and R
8 together with a carbon atom to which they are attached form C
3-15 cycloalkane ring, and C
3-15 cycloalkane ring formed by combining R
7 and R
8 may be substituted with one to three C
1-6 alkyls, and the resulting compound may be subjected to Step B-3.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0017)
[0186] In the formulae, R
7c, R
7e and R
7d existing in a number of n8 are each independently a hydrogen atom or C
1-6 alkyl, and n8 is an integer of 0 to 3.
[0187] The base includes, for example, metal hydrides such as sodium hydride, potassium
hydride, lithium bis(trimethylsilyl)amide (LiHMDS), and sodium bis(trimethylsilyl)amide
(NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA),
and lithium 2,2,6,6-tetramethylpyrrolidide, and KHMDS is preferred.
[0188] The solvent includes, for example, ether-based solvents such as THF, diethyl ether
and dioxane, amide-based solvents such as N,N-dimethyl acetamide (DMA), N,N-dimethylimidazolidinone
(DMI), DMF, N,N'-dimethylpropyleneurea (DMPU), and an amide-based solvent such as
DMPU is preferred.
[0189] The reaction temperature is, for example, -20°C to 40°C, preferably -10°C to 10°C.
[0190] The reaction time is, for example, 30 min. to 8 h., preferably 1 h. to 4 h.
<General production method C>
Step C-1:
[0192]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0018)
[0193] Compound f (or Compound p) and Compound bf may be condensed using a condensation
agent in the presence of a base, and Compound (Ia) may be obtained.
[0194] Examples of the condensation agent include BOP-based condensation agents such as
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(pyrrolizino)phosphonium
hexafluorophosphate (PyBOP(Registered Trademark)), PyAOP, BroP, PyCloP, PyBroP(Registered
Trademark), DEPBT; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
n-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium
hexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate (Oxyma). HATU is
preferred.
[0195] Examples of the base include tertiary amines (triethyl amine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine,
etc.), and a tertiary amine such as diisopropylethylamine is preferred.
[0196] Examples of the solvent include ether-based solvents such as THF, diethyl ether and
dioxane, aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide
(DMF), dimethylacetamide, and 1-methyl-2-pyrrolidinone, and an aprotic polar solvent
such as DMF is preferred.
[0197] The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C.
[0198] The reaction time is, for example, 1 min. to 10 h., preferably 30 min. to 5 h.
[0199] Note that Compound (Ia) may be obtained by changing the order of the steps, for example,
by sequentially subjecting Compound d to Step A1-5, Step C-1, Step A1-4, sequentially
subjecting Compound ba to Step B-2, Step B-3, Step B-4, Step B-5, Step C-1, and Step
B-1.
[0200] Further, the compound represented by Formula (I) may be brought in contact with or
reacted with an acid or base that may be used in the production of pharmaceutical
preparations to obtain the salt thereof. The salt may be any pharmaceutically acceptable
salt, and examples of such salts include inorganic acid salts (hydrochloric acid salt,
hydrobromic acid salt, hydroiodic acid salt, sulfuric acid salt, phosphoric acid salt,
etc.), sulfonic acid salts (methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic
acid salt, toluene sulfonic acid salt, etc.), carboxylic acid salts (formic acid salt,
acetic acid salt, oxalic acid salt, maleic acid salt, fumaric acid salt, citric acid
salt, malic acid salt, succinic acid salt, malonic acid salt, gluconic acid salt,
mandelic acid salt, benzoic acid salt, salicylic acid salt, fluoroacetic acid salt,
trifluoroacetic acid salt, tartaric acid salt, propionic acid salt, glutaric acid
salt, adipic acid salt, nicotinic acid salt, etc.), alkali metal salts (lithium salt,
sodium salt, potassium salt, cesium salt, rubidium salt, etc.), alkali earth metal
salts (magnesium salt, calcium salt, etc.), ammonium salts (ammonium salt, alkylammonium
salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.),
and basic amino acid salts (lysine salt, arginine salt, etc.), and alkali metal salts
and alkali earth metal salts are preferred, and sodium salts and calcium salts are
even more preferred. For example, the free form of a compound represented by Formula
(I) may be suspended or dissolved in alcohol, such as methanol, and ethanol, or acetonitrile,
acetone, dimethylsulfoxide, etc. and a basic aqueous solution containing sodium ion
from sodium hydroxide, etc., a methanol solution containing sodium methoxide, or an
ethanol solution containing sodium ethoxide is added thereto, to obtain a sodium salt
of a compound represented by Formula (I). The reaction temperature is, for example,
0°C to 80°C, preferably 20°C to 60°C.
[0201] The compound represented by Formula (1) or a salt thereof may be a solvate, or a
non-solvate. The solvent contained in a solvate may be either water or an organic
solvent. Alcohols (e.g. methanol, ethanol, n-propanol), dimethylformamide, acetonitrile,
acetone, dimethylsulfoxide may be used as the organic solvent. The compound represented
by Formula (I) and a salt thereof may be preferably used in the form of a hydrate,
and it is also preferably used in the form of a non-solvate. The proportion of the
solvent molecule (preferably a water molecule) against a single molecule compound
represented by Formula (I) or a salt thereof is, for example, 0.1 to 10, and 0.5 to
6 is more preferred. Further, the proportion may fluctuate by humidity, the production
method, and the production season.
[0202] The solvate of a compound represented by Formula (I) or a salt thereof may be obtained
by a common method, such as precipitating the compound represented by Formula (1)
or a salt thereof from a solvent. Further, the hydrate may be obtained by precipitating
a compound represented by Formula (I) or a salt thereof from a water-containing organic
solvent.
[0203] The solvate of a compound represented by Formula (I) or a salt thereof may be transformed
to a compound represented by Formula (I) or a salt thereof by a common method such
as heating under reduced pressure.
[0204] A compound used as a pharmaceutical agent is preferably the compound represented
by Formula (I) per se (free form), a hydrate of the free form, a salt of the free
form, and a hydrate of salt, more preferably, a free form, a hydrate of the free form,
a sodium salt of the free form, a hydrate of a sodium salt, a calcium salt of the
free form, and a hydrate of the calcium salt.
[0205] The compound represented by Formula (I) or a salt thereof, or a solvate of either
the compound or a salt of the compound, of the present invention may be used in a
form of a crystal, or in an amorphous state.
[0206] The present invention includes all stereoisomers of the compound represented by Formula
(I) (e.g. enantiomer, diastereomer (including cis- and trans- geometric isomer)),
the racemic form of the isomers, and other mixtures. For example, the compound of
the present invention may have one or more asymmetric center, and the present invention
includes a racemic mixture, a diastereomer mixture, and enantiomers of such compound.
[0207] The present invention includes an embodiment in which an atom constituting the compound
molecule of the present invention represented by Formula (I) is an isotope, and includes
an embodiment in which at least one atom is substituted with an atom having the same
atomic number (proton number) and a different mass number (sum of protons and neutrons).
Examples of isotopes included in the compound of the present invention include hydrogen
atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine
atom, chlorine atom, which respectively include
2H,
3H,
13C,
14C,
15N,
17O,
18O,
31P,
32P,
35S,
18F,
36Cl. In particular, radioisotopes which emit radiation as they decay, such as
3H or
14C, are useful in pharmaceutical preparations or in vivo topographic tests of compounds.
The stable isotope neither decays nor changes in their amount, nor have radioactivity,
so they can be used safely. When the atom constituting the compound molecule of the
present invention is an isotope, it may be transformed according to the common method
by replacing the reagent used in synthesis with a reagent containing the corresponding
isotope.
[0208] The compound of the present invention, a salt thereof, or a solvent of these has
a GLP1 receptor agonist effect and a blood glucose level reduction effect, and it
may be used for the prevention or therapy of non-insulin-dependent diabetes mellitus
(Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes
mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension, hyperlipidemia,
arteriosclerosis, myocardial infarction, coronary heart disease, brain infarction,
non-alcoholic steatohepatitis, Parkinson's disease, or dementia, by administering
it to patients in the form of a pharmaceutical composition in pharmacologically effective
amount by an appropriate administration method.
[0209] "Diabetes" in the present invention is a state or a disease in which the metabolism
for generating and using glucose becomes deficient due to a failure in maintaining
an appropriate blood glucose level in the body, and encompasses insulin-dependent
diabetes mellitus (Type 1 diabetes) and non-insulin-dependent diabetes mellitus (Type
2 diabetes). "Hyperglycemia" refers to a state in which the plasma glucose level while
fasting or after administration of glucose is higher than the normal value (e.g. 80
to 110 mg/dL in human while fasting), and it is a typical symptom of diabetes.
[0210] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance
and insulin hyposecretion.
[0211] "Diabetic complication" is a complication caused by diabetes or hyperglycemia, and
it may be acute complex or chronic complex. The term "acute complex" includes ketoacidosis,
and infectious disease (e.g. skin infection, soft tissue infection, biliary system
infection, respiratory system infection, urinary tract infection), and the "chronic
complex" includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy
(e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and
gangrene. Major diabetes complexes include diabetic retinopathy, diabetic nephropathy,
and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction and
angina pectoris. "Dementia" includes, for example, Alzheimer's disease, vascular dementia,
and diabetic dementia.
[0212] The administration method may be systemic administration including oral administration,
rectal administration, intravenous administration, intramuscular administration, subcutaneous
administration, intravaginal administration, intraperitoneal administration, intravesical
administration, and aspiration, as well as local administration by ointment, gels,
and cream.
[0213] When using the compound of the present invention, a salt thereof, or a solvate of
either the compound or a salt of the compound in the form of a pharmaceutical composition,
it is normally formulated into a certain pharmaceutical formulation (dosage form).
Examples of such pharmaceutical formulations include a tablet, a capsule, granules,
powders, subtle granules, pills, aqueous or non-aqueous solution or suspension. Further,
the compound of the present invention, a salt thereof, or a solvate of either the
compound or a salt of the compound may also be used in the form of various controlled
release preparations. Examples of such controlled release preparations include, for
example, those to be imbedded in the body, those applied to the oral mucosa or nasal
mucosa. The solution or suspension may be filled in containers suited for dividing
into respective administration amounts to be stored.
[0214] The various pharmaceutical formulations may be produced by a well known method by
mixing the compound of the present invention, a salt thereof, or a solvate of either
the compound or a salt of the compound and a pharmaceutically acceptable additive.
Examples of such additives include, for example, an excipient, a lubricant (a coating
agent), a binding agent, a disintegrator, a stabilizer, correctives, a base, a dispersant,
a diluent, a surfactant, or an emulsifier.
[0215] Examples of an excipient include starch (starch, potato starch, corn starch, etc.),
lactose, crystalline cellulose, and dicalcium phosphate.
[0216] Examples of a lubricant (coating agent) include ethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin. Examples
of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are
the same as the above excipient.
[0217] Examples of a disintegrator include chemically modified starch and cellulose, such
as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone,
and compounds that are the same as the above excipient.
[0218] Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and propyl
paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic
acid; and sorbic acid.
[0219] Examples of a correctives include sweetener, acidulant, and flavor, that are normally
used.
[0220] Examples of a base include fats such as lard; vegetable oil such as olive oil and
sesame oil; higher alcohols such as stearyl alcohol, and cetanol; animal oil; lanolin
acid; Vaseline; paraffin; bentonite; glycerin; and glycol oil.
[0221] Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth,
methyl cellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum
monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.
[0222] Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol,
purified water, distilled water, etc.
[0223] Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate,
lauromacrogol.
[0224] The content of the compound of the present invention, a salt thereof, or a solvate
of either the compound or a salt of the compound in the pharmaceutical formulation
differs by the dosage form, but it is generally 0.01 to 100 wt%.
[0225] The pharmaceutical formulation may contain one type or two or more types of the compound
of the present invention, a salt thereof, or a solvate of either the compound or a
salt of the compound.
[0226] When using the compound of the present invention, a salt thereof, or a solvate of
either the compound or a salt of the compound as a preventative agent or a therapeutic
agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity, the
amount to be administered may be appropriately determined according to the severity
of the symptom, the age, the body weight, the relative health state, whether other
drugs are combined, and the method of administration. For example, when the subject
of administration is a homeotherm, particularly a human, the dosage per day is 0.01
to 10000 mg, preferably 0.1 to 1000 mg, in oral administration, and 0.001 to 3000
mg, preferably 0.01 to 300 mg in a non-oral administration. Note that the above dosage
may be administered once per a day to a few weeks, or it may be divided into two or
more times per day.
[0227] The effective amount of the compound of the present invention, a salt thereof, or
a solvate of either the compound or a salt of the compound means a therapeutic effective
amount or a preventative effective amount, and it may be appropriately determined
according to the severity of the symptom, the age, the body weight, the relative health
state, whether other drugs are combined, and the method of administration
EXAMPLES
[0228] The content of the present invention is explained in more detail by the following
Examples and Reference Examples. All starting materials and reagents were obtained
from commercial suppliers or synthesized by commonly known methods. A room temperature
(rt) is a temperature of 5 to 35°C. The silica gels that were used were SHOKO Scientific
Purif-Pack(Registered Trademerk) SI 60 µm (Shoko Scientific Co., Ltd.), Biotage (Registered
Trademark) SNAP Ultra Silica Cartridge (Biotage), or SNAP KP-Sil Cartridge (Biotage),
reversed-phase silica gel was Wakosil (Registered Trademark) 25C18 (Wako Pure Chemical
Industries, Ltd.), or Biotage (Registered Trademark) SNAP Ultra C18 Cartridge (Biotage).
The HPLC purification of the compound was performed using AutoPurification HPLC/MS
System (Waters) or Preprative HPLC system with injection/fractionation function (Gilson).
The
1H-NMR spectrum was measured using or not using Me
4Si as an inner reference material, and using ECP-400 (JEOL), Agilent 400-MR (Agilent
Technologies Japan, Ltd), AVANCE3 300MHz (Bruker) or AVANCE3 600MHz Cryo-TCI (Bruker)
(s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet,
ddd=double double doublet, m=multiplet). The chemical shift of the NMR data uses Me
4Si or deuterated solvent as a reference, and is presented using ppm (parts per million,
δ), and the coupling constant (J) was shown using Hz (Hertz). LC/MS was carried out
by measuring the retention time and performing mass spectrometry using the device
and the analysis condition of Table 1. Microwave was irradiated using InitiatorTM
(Biotage). The mass spectrometry in LC/MS was performed using the following mass spectrometers:
SQD (Waters), SQD2 (Waters), 2020 (Shimadzu), or 2010EV (Shimadzu).
[Table 1]
[0229]
Table 1. Device and Analysis Condition used for LC/MS
LC/MS Analysis Condition No. |
Device |
Column |
Mobile phase, gradient and flow rate |
SMD-FA05-1 |
nexera/20 20 |
Speed Core C 18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-FA05-2 |
nexera/20 20 |
Metoric Core C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.5min.)→0/100(0.5 min.), 1 mL/min. |
SMD-FA05-3 |
nexera/20 20 |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.5 min.)→0/100(0.7 min.), 1 mL/min. |
SMD-FA05-long |
nexera/20 20 |
Speed Core C 18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =05/95→0/100(4.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-FA10-1 |
UFLCXR /2020 |
Phenomenex kinetex C18 3 .0mmI.D.x50mm, 2.6µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(1.2 min.)→0/100(0.5 min.), 1.5 mL/min. |
SMD-FA10-2 |
UFLCXR /2020 |
Kinetex XB-C 18 3.0mmI.D.x50mm, 2.6µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(1.2 min.)→0/100(0.5 min.), 1.5 mL/min. |
SMD-FA10-3 |
UFLCXR /2020 |
Kinetex XB-C 18 3.0mmI.D.x50mm, 2.6µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(1.1 min.)→0/100(0.7 min.), 1.5 mL/min. |
SMD-FA10-4 |
UFLCXR /2020 |
Acquity BEH C18 2.1mmI.D.x50mm, 1.7µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(1.1 min.)→0/100(0.5 min.), 0.7 mL/min. |
SMD-FA10-5 |
Nexera/2 020 |
Accucore 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(1.1 min.)→0/100(0.5 min.), 1.0 mL/min. |
SMD-FA1060-1 |
UFLCXR /2020 |
Kinetex XB-C 18 3.0mmI.D.x50mm,2. 6µm |
0.1%FA H2O/0.1%FA MeCN =90/10-40/60(4.0 min.)→5/95(0.5 min.), 1.5 mL/min. |
SMD-FA10-long |
UFLCXR /2020 |
Phenomenex kinetex C18 3.0mmI.D.x50mm,2. 6µm |
0.1%FA H2O/0.1%FA MeCN =90/10→0/100(4.5 min.)→0/100(1.3 min.), 1.1 mL/min. |
SMD-TFA05-1 |
nexera/20 20 |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.05%TFA H2O /0.05%TFA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-TFA05-2 |
nexera/20 20 |
Metoric Core C18 2.1mmI.D.x50mm, 2.7µm |
0.05%TFA H2O /0.05%TFA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-TFA05-3 |
nexera/20 20 |
Kinetex 1.7u C18 2.1mmI.D.x50mm, 1.7µm |
0.05%TFA H2O /0.05%TFA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-TFA05-4 |
nexera/20 20 |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.05%TFA H2O /0.05%TFA MeCN =95/5→0/100(1.1 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-TFA05-5 |
UFLCXR /2020 |
Shim-pack XR-ODS 3.0mmI.D.x50mm, 2.2µm |
0.05%TFA H2O/0.05%TFA MeCN =95/5→0/100(1.2 min.)→0/100(1.0 min.), 1 mL/min. |
SMD-TFA05-6 |
UFLCXR /2020 |
Shim-pack XR-ODS 3.0mmI.D.x50mm,2. 2µm |
0.05%TFA H2O/0.05%TFA MeCN =95/5→0/100(2.2 min.)→0/100(1.0 min.), 1 mL/min. |
SMD-FA05-RP |
nexera/20 20 |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-FA50-RP |
nexera/20 20 |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =50/50→0/100(1.0 min.)→0/100(1.0 min.), 1 mL/min. |
SMD-TFA05-RP |
nexera/20 20 |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.05%TFA H2O/0.05%TFA MeCN =95/5→0/100(1.5 min.)→0/100(0.5 min.), 1 mL/min. |
SMD-TFA50-RP |
nexera/20 20 |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.05%TFA H2O/0.05%TFA MeCN =50/50→0/100(1 min.)→0/100(1 min.), 1ml/min. |
SQD-FA05-1 |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.0 min.)→0/100(0.4 min.), 0.9 mL/min. |
SQD-FA05-2 |
Aquity UPLC-I-Class/SQ D |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1 %FA MeCN =95/5→0/100(1.0 min.)→0/100(0.4 min.), 1 mL/min. |
SQD-FA05-3 |
Aquity UPLC/S QD |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.0 min.)→0/100(0.4 min.), 1 mL/min. |
SQD-FA05-4 |
Aquity UPLC/S QD2 |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(1.0 min.)→0/100(0.4 min.), 1 mL/min. |
SQD-FA50-1 |
Aquity UPLC-I-Class/SQ D |
Ascentis Express RP-Amide 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =50/50-0/100(0.7 min.)→0/100(0.7 min.), 1 mL/min. |
SQD-AA05-1 |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 5µm |
10mMAcONH4 H2O/MeOH =95/5→0/100(1 min.)→100(0.4 min.), 1 mL/min. |
SQD-AA05-2 |
Aquity UPLC/S QD |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
10mMAcONH4 H2O/MeOH =95/5→0/100(1 min.)→100(0.4 min.), 1 mL/min. |
SQD-AA50-1 |
Aquity UPLC/S QD |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
10mMAcONH4 H2O/MeOH =50/50→0/100(0.7 min.)→100(0.7 min.), 1 mL/min. |
SQD-FA05-long |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→0/100(4.5 min.)→0/100(0.5 min.), 1 mL/min. |
SQD-FA0550-long |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 2.7µm |
0.1%FA H2O/0.1%FA MeCN =95/5→5/50(4.5 min.)→0/100(0.01 min.)→0/100(0.49 min.), 1 mL/min. |
SQD-AA50-long |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 5µm |
10mMAcONH4 H2O /MeOH =50/50→0/100(4.5 min.)→100(0.5 min.), 1 mL/min. |
SQD-AA0550-long |
Aquity UPLC-I-Class/SQ D |
Ascentis Express C18 2.1mmI.D.x50mm, 5µm |
10mMAcONH4 H2O /MeOH =95/5→50/50(4.5 min.)→0/100(0.01 min.)→0/100(0.49 min.), 1 mL/min. |
<Example 1> Synthesis of 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 1)
[0230]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0019)
<Step 1-1>
Potassium [(5-Cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] Compound 1b)
[0231] To a tetrahydrofuran (THF) (179 mL) solution of 3-(2-cyanoethylamino)propanenitrile
(Compound 1a, 22.0 g, 179 mmol) was added a THF solution (179 mL) of 1M potassium
tert-butoxide and the mixture was stirred at room temperature for 1 h. The reaction
mixture was filtered by washing with THF (50 mL), and then the filtrate was dried
under reduced pressure to obtain the titled Compound 1b (23.8 g, yield 83%) as a light
brown solid.
[0232] LC/MS Mass Spectrometery: m/z 124 ([M+H]
+).
[0233] LC/MS Retention Time: 0.14 min. (Analysis Condition: SMD-FA05-1).
[0234] 1H-NMR (400MHz, MeOH-d
4) δ:3.33 (2H, t, J=1.3 Hz), 2.90 (2H, t, J=5.9 Hz), 2.21 (2H, tt, J=5.9, 1.3 Hz).
<Step 1-2>
tert-Butyl 3-amino-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolol4,3-c]pyridine-5-carboxylate
(Compound 1d)
[0235] To an ethanol (57.9 mL) solution of 3,5-dimethylphenylhydrazine hydrochloride (Compound
1c, 5.00 g, 29.0 mmol) and Compound 1b obtained in Step 1-1 (4.67 g, 29.0 mmol) was
added 2N hydrochloric acid (23.2 mL, 46.3 mmol), and the mixture was stirred at 50°C
for 1 h. After the reaction mixture was cooled to 0°C, 5M sodium hydroxide aqueous
solution (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were
added and the mixture was stirred at 0°C for 1 h. Water was added to the reaction
mixture and extraction was performed using ethyl acetate, then the organic layer was
washed with brine and dried with anhydrous magnesium sulfate. After filtration, the
filtrate was concentrated under reduced pressure, and the residue was purified by
a silica gel column chromatography (ethyl acetate/hexane=0:1 to 1:1) to obtain the
titled Compound 1d (7.82 g, yield 79%) as a pale yellow solid.
[0236] LC/MS Mass Spectrometry: m/z 343 ([M+H]
+)
∘
[0237] LC/MS retention time: 0.99 min. (Analysis condition: SMD-FA05-3).
<Step 1-3>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolol4,3-c1pyridine-5-carboxylate(Compound
1f)
[0238] To a pyridine (7.39 mL) solution of Compound 1d (2.53 g, 7.39 mmol) obtained in Step
1-2 was added 2-isocyanato-1,1-dimethoxyethane (Compound 1e, 1.94 g, 14.8 mmol), and
the mixture was stirred at room temperature. After 3 hours and 15 minutes, diethylamine
(1.08 g, 14.8 mmol) was added and the mixture was stirred at room temperature for
5 min., then water (50.6 mL) was added, and the resulting mixture was stirred at room
temperature for 20 min. The reaction mixture that had become a suspension was filtered,
and the obtained solid was washed with water (12.7 mL) then dried under reduced pressure
to obtain the titled Compound 1f (3.20 g, yield 91%) as a pale-yellow solid.
[0239] LC/MS mass spectrometry: m/z 474 ([M+H]
+).
[0240] LC/MS retention time: 0.78 min. (Analysis Condition: SQD-FA05-1).
<Step 1-4>
3-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-y]-1H-imidazol-2-one
(Compound 1g)
[0241] To Compound 1f (158 mg, 0.334 mmol) obtained in Step 1-3 was added formic acid (3.84
mL, 100 mmol), and the mixture was stirred at room temperature for 21 h. The reaction
mixture was concentrated under reduced pressure, and toluene was added and the solvent
was removed by evaporation under reduced pressure. Dichloromethane (1 mL) was added
to the residue to dissolve the residue, and then hydrogen chloride (4M dioxane solution,
0.835 mL, 3.34 mol) was added at room temperature. The reaction mixture was concentrated
under reduced pressure. Toluene was added and the solvent was removed by evaporation
under reduced pressure to obtain a crude product (176 mg) of the titled Compound 1g.
[0242] LC/MS mass spectrometry: m/z 310 ([M+H]
+).
[0243] LC/MS retention time: 0.39 min. (Analysis Condition: SQD-FA05-3).
<Step 1-5>
4-Bromo-2-ethyl-3-methylpyridine (Compound 1i)
[0244] A THF (75.0 mL) solution of 4-bromo-2,3-dimethylpyridine (Compound 1h, 7.05 g, 37.9
mmol) was cooled to -78°C, and then 1.11 M lithium diisopropylamide n-hexane-THF solution
(35.8 mL, 39.8 mmol) was added slowly. The reaction mixture was stirred at -78°C for
5 min., and then iodomethane (2.84 mL, 45.5 mmol) was added. The reaction mixture
was stirred at -78°C for 5 min., and warmed slowly to room temperature. Then, the
reaction mixture was stirred for 30 min. and the solvent was removed by evaporation
under reduced pressure. The residue was purified by silica gel column chromatography
(dichloromethane /ethyl acetate), and the titled Compound 1i (6.98 g, yield 92%) was
obtained as an orange oillike material.
[0245] LC/MS mass spectrometry: m/z 200 ([M+H]
+).
[0246] LC/MS retention time: 0.38 min. (Analysis Condition: SQD-FA05-3).
<Step 1-6>
Ethyl 5-bromo-1-[(1S, 2S)-1-cyano-2-methylcyclopropyl]indole-2-carboxylate (Compound
11)
[0247] The N,N'-dimethylpropyleneurea (117 mL) solution of ethyl 5-bromo-1-(cyanomethyl)indole-2-carboxylate
(Compound 1j, 3.60 g, 11.7 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide
(Compound 1k, 4.86 g, 35.2 mmol) was de-aerated under reduced pressure, then nitrogen
was introduced in the vessel and the mixture was cooled to 0°C. Under nitrogen atmosphere,
a THF solution (46.9 mL, 46.9 mmol) of 1.0 M potassium bis(trimethylsilyl)amide was
added dropwise slowly. The reaction mixture was stirred at 0°C for 2.5 h., then formic
acid (5.30 mL, 141 mmol) was added and extraction was performed using a mixture of
hexane/ethyl acetate (1:3). The organic layer was washed three times with water, twice
with a saturated aqueous solution of sodium hydrogen carbonate, and once with brine,
and then dried with sodium sulfate. After filtration, the filtrate was concentrated
under reduced pressure and the residue was purified by silica gel column chromatography
(ethyl acetate/hexane =1: 19 to 1:4) to obtain the titled Compound 11 (1.70 g, yield
42%) as a white solid.
[0248] LC/MS mass spectrometry: m/z 347 ([M+H]
+).
[0249] LC/MS retention time: 0.69 min. (Analysis Condition: SQD-AA50-1).
<Step 1-7>
Ethyl 1-1(1S,2S)-1-cyano-2-methylcyclopropyl1-5- (2-ethyl-3-methylpyridin-4-yl)indole-2-carboxylate
(Compound 1m)
[0250] The dioxane (44 mL) suspension of Compound 11 (2.70 g, 7.78 mmol) obtained in Step
1-6, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.17 g, 8.55 mmol)
and potassium acetate (1.15 g, 11.7 mmol) were de-aerated under reduced pressure,
and then nitrogen was introduced in the vessel. Under nitrogen atmosphere, 1,1'-bis
(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (1.29
g, 1.56 mmol) was added, and the mixture was stirred at 100°C for 3 h. After the solution
was cooled to room temperature, 4-bromo-2-ethyl-3-methylpyridine (Compound 1i, 2.33
g, 11.7 mmol), sodium carbonate (2.47 g, 23.3 mmol), and water (7.4 mL) were added
to the solution, and then the solution was subjected to deaeration under reduced pressure.
[0251] Nitrogen was introduced in the vessel, and the solution was stirred at 100°C for
2 h. The solution was cooled to room temperature, and then water (5.4 mL), and N-acetyl
cysteine (0.635 g, 3.89 mmol) were added. The mixture was stirred for 0.5 h. The reaction
mixture was subjected to extraction with ethyl acetate, and the organic layer was
washed once with brine, and then dried using sodium sulfate. After filtration, the
filtrate was concentrated under reduced pressure and the residue was purified by silica
gel column chromatography (ethyl acetate/hexane = 1:19 to 2:3) to obtain the titled
Compound 1m (2.92 g, yield 97%) as a pale yellow gum-like product.
[0252] LC/MS mass spectrometry: m/z 388 ([M+H]
+).
[0253] LC/MS retention time: 1.06 min. (Analysis Condition: SQD-AA05-2).
<Step 1-8>
Ethyl 5-(2-ethyl-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylate
Compound 1n)
[0254] To a dimethylsulfoxide (DMSO) (2.9 mL) solution of Compound 1m (0.225 g, 0.581 mmol)
obtained in Step 1-7 was added 50% hydroxyamine aqueous solution (0.356 mL, 5.81 mmol),
and the mixture was stirred at room temperature for 17 h. Ethyl acetate (50 mL) was
added, the mixture was washed with water (10 mL) and brine (10 mL), and then dried
with magnesium sulfate. After the mixture was filtered, the filtrate was concentrated
under reduced pressure, and the obtained residue was dissolved in DMSO (1.9 mL). Then,
carbonyl diimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundec-7-ene (0.219 mL,
1.45 mmol) were added and the resulting mixture was stirred at room temperature for
0.5 h. Formic acid was added to the mixture, which was then purified by reversed-phase
chromatography (acetonitrile/water, 0.1% formic acid) to obtain the titled Compound
1n (169 mg, yield 65%) as a white powder.
[0255] LC/MS mass spectrometry: m/z 447 ([M+H]
+).
[0256] LC/MS retention time: 0.80 min. (Analysis Condition: SMD-FA05-3).
<Step 1-9>
5-(2-Ethyl-3-methylpyridin-4-yl)-1-1(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl1indole-2-carboxylic
acid (Compound 1o)
[0257] To a DMSO (40 mL) solution of Compound 1n (3.61 g, 8.08 mmol) obtained in Step 1-8
was added 2M sodium hydroxide aqueous solution (10.1 mL, 20.2 mmol), and the mixture
was stirred at room temperature for 1.5 h. Formic acid was added to the mixture, which
was then purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic
acid) to obtain the titled Compound 1o (3.38 g, yield 100%) as a white powder.
[0258] LC/MS mass spectrometry: m/z 419 ([M+H]
+).
[0259] LC/MS retention time: 0.83 min. (Analysis Condition: SQD-AA05-2).
<Step 1-10>
3-1(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3- (2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-
(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 1p)
[0260] To a N,N'-dimethylformamide (DMF) (24.1 mL) solution of Compound 1g (1.25 g, 3.61
mmol) obtained in Step 1-4, Compound 1o (1.59 g, 3.80 mmol) obtained in Step 1-9,
and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium hexafluorophosphate
(1.51 g, 3.98 mmol) was added diisopropylethylamine (3.15 mL, 18.1 mmol), and the
mixture was stirred at room temperature for 30 min. The reaction mixture was directly
purified by reversed-phase column chromatography (acetonitrile/water, 0.1% formic
acid) and the titled Compound 1p (2.44 g, yield 95%) was obtained as a light brown
foam.
[0261] LC/MS mass spectrometry: m/z 710 ([M+H]
+).
[0262] LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).
<Step 1-11>
3-[(1S,2S)-1-[2-[2-(3,5-Dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 1)
[0263] To a N-methylpyrrolidone (0.188 mL) suspension of Compound 1p (20 mg, 0.028 mmol)
obtained in Step 1-10, 5-bromo-1-methylindazole (Compound 1q, 11.9 mg, 0.056 mmol),
(1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol) and potassium
carbonate (11.7 mg, 0.085 mmol) was added copper (I) iodide (1.1 mg, 0.0056 mmol)
at room temperature, and the mixture was stirred under nitrogen atmosphere at 130°C
for 3 h. The reaction mixture was purified by reversed-phase silica gel chromatography
(acetonitrile/water, 0.1% formic acid), and the titled Compound 1 (17.2 mg, yield
73%) was obtained as a light brown foam.
[0264] LC/MS mass spectrometry: m/z 840 ([M+H]
+).
[0265] LC/MS retention time: 1.12 min. (Analysis Condition: SMD-TFA05-3).
<Examples 2 to 50>
[0267] The compounds in Table 2-1 have rotational isomers, and by way of example, the
1H-NMR of Example 2 compound is shown below.
Rotational Isomer A
[0268] 1H-NMR (600 MHz, CDCl
3) δ: 11.29 (1H, s), 8.40 (1H, d, J=5.2 Hz), 7.93 (1H, s), 7.74 (1H, d, J=1.5 Hz),
7.70 (1H, d, J=8.6 Hz), 7.56 (1H, s), 7.45 (1H, dd, J=9.0, 1.5 Hz), 7.38 (1H, d, J=9.0
Hz), 7.28 (1H, m), 7.14 (1H, d, J=5.2 Hz), 7.04 (2H, d, J
HF=5.9 Hz), 6.82 (1H, s), 6.59 (1H, d, J=3.0 Hz), 6.08 (1H, d, J=3.0 Hz), 4.96 (1H,
d, J=16.0 Hz), 4.92 (1H, d, J=16.0 Hz), 4.69 (1H, ddd, J=13.1, 4.4, 4.4 Hz), 4.06
(3H, s), 3.75 (1H, ddd, J=13.1, 9.5, 5.0 Hz), 3.07 (2H, m), 2.97 (2H, q, J=7.6 Hz),
2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H, m), 1.37 (3H, t, J=7.6 Hz), 1.17
(3H, d, J=5.6 Hz).
Rotational Isomer B
[0269] 1H-NMR (600 MHz, CDCl
3) δ: 11.29 (1H, s), 8.44 (1H, d, J=5.2 Hz), 8.04 (1H, s), 7.90 (1H, d, J=1.4 Hz),
7.73 (1H, d, J=8.8 Hz), 7.63 (1H, dd, J=9.0, 1.4 Hz), 7.60 (1H, s), 7.51 (1H, d, J=9.0
Hz), 7.30 (1H, m), 7.20 (1H, d, J=5.2 Hz), 7.11 (2H, d, J
HF=6.0 Hz), 6.81 (1H, s), 6.71 (1H, d, J=3.0 Hz), 6.22 (1H, d, J=3.0 Hz), 5.24 (1H,
d, J=16.3 Hz), 4.64 (1H, d, J=16.3 Hz), 4.45 (1H, ddd, J=13.5, 4.6, 4.0 Hz), 4.12
(3H, s), 3.87 (1H, ddd, J=13.5, 10.2, 3.8 Hz), 3.17 (1H, ddd, J=15.5, 10.2, 4.6 Hz),
3.02 (1H, m), 3.00 (2H, q, J=7.6 Hz), 2.30 (3H, s), 2.28 (6H, s), 1.96 (1H, dd, J=6.0
Hz), 1.64 (1H, m), 1.58 (1H, dd, J=9.4, 6.0 Hz), 1.39 (3H, t, J=7.6 Hz), 1.19 (3H,
d, J=6.1 Hz).
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0040)
[0270] The 2-oxoimidazole compound (3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 2g) used in the synthesis of Example Compounds 2 to 5 was synthesized by
the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0041)
<Step 2-1>
4-Fluoro-3,5-dimethylaniline hydrochloride (Compound 2b)
[0271] 4-Fluoro-3,5-dimethylaniline (Compound 2a, 3.97 g, 28.5 mmol) was added at room temperature
while concentrated hydrochloric acid (20 mL) and water (20 mL) were stirred. The reaction
mixture was stirred for 1 h. at that temperature, then the solid in the reaction mixture
was collected by filtration and dried. To the obtained solid was added methoxycyclopentane
(20 mL), and the mixture was stirred at 50°C for 1 h., then at room temperature for
1.5 h. The precipitated solid was collected by filtration and washed with methoxycyclopentane
(12 mL). The obtained solid was dried under reduced pressure to obtain titled Compound
2b (4.88 g, yield 97%) as an off-white solid.
[0272] The compound was directly put to use in the next step, <Step 2-2>.
<Step 2-2>
(4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 2c)
[0273] To Compound 2b (1.00 g, 5.69 mmol) obtained in Step 2-1 was added concentrated hydrochloric
acid (10 mL), and an aqueous solution (2.4 mL of water) of sodium nitrite (511 mg,
7.40 mmol) was added over a period of 1 min. while the mixture was stirred vigorously
at 0°C, then the mixture was stirred at 0°C for 30 min. Then, an aqueous solution
(2.4 mL of water) of tin(II) chloride (2.27 g, 12.0 mmol) was added over a period
of 2 min. Further, water (7 mL) was added, and the mixture was stirred at room temperature
for 1 h. The solid in the reaction mixture was collected by filtration and washed
with water (2 mL). Then, it was dried to obtain the titled Compound 2c (1.75 g, yield
77%, content 48%) as a grey solid.
[0274] LC/MS mass spectrometry: m/z 155 ([M+H]
+).
[0275] LC/MS retention time: 0.54 min. (Analysis Condition: SMD-FA05-1).
<Step 2-3>
tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-clpyridine-5-carboxylate Compound 2d)
[0276] The titled compound was obtained from Compound 1b obtained in Step 1-1 and Compound
2c obtained in Step 2-2 by performing an operation similar to Step 1-2 of Example
1 using an appropriate reagent.
[0277] LC/MS mass spectrometry: m/z 361 ([M+H]
+).
[0278] LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).
<Step 2-4>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolol4,3-c1pyridine-5-carboxylate
Compound 2e)
[0279] The titled compound was synthesized from Compound 2d obtained in Step 2-3 by performing
an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
[0280] LC/MS mass spectrometry: m/z 492 ([M+H]
+).
[0281] LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-3).
<Step 2-5>
3-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pylidin-3-yl]-1H-imidazol-2-one
hydrochloride (Compound 2f)
[0282] The titled compound was synthesized from Compound 2e obtained in Step 2-4 by performing
an operation similar to Step 1-4 of Example 1 using an appropriate reagent.
[0283] LC/MS mass spectrometry: m/z 328 ([M+H]
+).
[0284] LC/MS retention time: 0.61 min. (Analysis Condition: SMD-FA05-3).
<Step 2-6>
3-[(1S,2S)-1-[5-(2-Ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 2g)
[0285] The titled compound was synthesized from Compound 2f obtained in Step 2-5 and Compound
1o obtained in Step 1-9 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0286] The 2-oxoimidazole compound (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 6i) used in the synthesis of Example Compound 6 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0042)
<Step 6-1>
5-Bromo-1-(cyanomethyl)-N-methyl-N-phenylindole-2-carboxamide (Compound 6c)
[0287] The titled compound was synthesized from 5-bromo-1-(cyanomethyl)indole-2-carboxylic
acid (Compound 6a) and N-methylaniline (Compound 6b) by performing an operation similar
to Step 1-10 of Example 1 using an appropriate reagent.
[0288] LC/MS mass spectrometry: m/z 368 ([M+H]
+).
[0289] LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-3).
<Step 6-2>
5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide
(Compound 6d)
[0290] The titled compound was synthesized from Compound 6c obtained in Step 6-1 by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0291] LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
[0292] 1H-NMR (400 MHz, DMSO-d
6) δ: 7.69 (1H, s), 7.65-7.25 (7H, m), 6.02 (1H, brs), 3.44 (3H, s), 3.31 (3H, d, J=9.5
Hz), 2.04-1.74 (3H, m).
<Step 6-3>
5-Bromo-N-methyl-1-[(1S,2S)-2-methyl-1- 5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide
(Compound 6e)
[0293] The titled compound was synthesized from Compound 6d obtained in Step 6-2 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0294] LC/MS mass spectrometry: m/z 467 ([M+H]
+).
[0295] LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-01).
<Step 6-4>
5-Bromo-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 6f)
[0296] A mixture of Compound 6e (9.70 g, 20.8 mmol) obtained in Step 6-3, potassium hydroxide
(11.7 g, 208 mmol), and methoxyethanol (41.5 mL) was stirred at 100°C for 4 h. 6N
Hydrochloric acid (51.9 mL) was added under ice cold condition, and the suspension
was stirred at room temperature for 30 min. The solid was collected by filtration
and washed with water (29.1 mL), then dried under reduced pressure to obtain the titled
Compound 6f (7.42 g, yield 95%) as a light brown solid.
[0297] LC/MS mass spectrometry: m/z 376 ([M-H]
-).
[0298] LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).
<Step 6-5>
5-(2-Methoxy-3-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 6h)
[0299] The DMSO (34.7 mL) suspension of Compound 6f (3.00 g, 7.93 mmol) obtained in Step
6-4, palladium(II) acetate (0.178 g, 0.793 mmol), dicyclohexyl (2',4',6'-triisopropyl-[1,
I'-biphenyl]-2-yl)phosphane (0.756 g, 1.587 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(3.02 g, 11.9 mmol), potassium phosphate (10.1 g, 47.6 mmol) was de-aerated at room
temperature under reduced pressure, then, nitrogen was introduced in the vessel. Under
nitrogen atmosphere, the suspension was stirred at 100°C for 0.5 h., then cooled to
room temperature. 4-Iodo-2-methoxy-3-methylpyridine (Compound 6g, 1.98 g, 7.93 mmol),
water (4.96 mL) were added to the solution, and the solution was subjected to deaeration
under reduced pressure. Nitrogen was introduced in the vessel, and the solution was
stirred at 100°C for 0.5 h. After cooling to room temperature, water (12.4 mL) and
formic acid (6 mL) were added to the solution. After filtration, the filtrate was
directly purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic
acid) to obtain the titled Compound 6h (1.83 g, yield 55%).
[0300] LC/MS mass spectrometry: m/z 421 ([M+H]
+).
[0301] LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
<Step 6-6>
3-1(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3- (2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-
(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 6i)
[0302] The titled compound was synthesized from Compound 2f obtained in Step 2-5 and Compound
6h obtained in Step 6-5 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0303] The halogen compound (1- (5-bromoindazol-1-yl)-2-methylpropan-2-ol, Compound 6l)
used in the synthesis of Example Compound 6 was synthesized by the following process.
<Step 6-7>
1-(5-Bromoindazol-1-yl)-2-methylpropan-2-ol (Compound 6k)
[0304]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0043)
[0305] 5-Bromoindazole (Compound 6j, 150 mg, 0.761 mmol) and 2,2-dimethyloxirane (Compound
6k, 274 mg, 3.81 mmol) were dissolved in 1-methylpyrrolidin-2-one (NMP) (1.52 mL),
to which potassium carbonate (526 mg, 3.81 mmol) was added. The solution was stirred
under microwave at 180°C for 30 min. Water was added to the reaction mixture, and
extraction was performed using ethyl acetate. The organic layer was washed with water,
and the solvent was removed by evaporation under reduced pressure. The resulting product
was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain
the titled Compound 6l (115 mg, yield 56%).
[0306] LC/MS mass spectrometry: m/z 269 ([M+H]
+).
[0307] LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).
[0308] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5- (2,2-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-
(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 7c) used in the synthesis of Example Compound 7 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0044)
<Step 7-1>
5-(2,2-Dimethylmorpholin-4-yl)-1-[(1S,2S)-2-methyl-1-5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 7b)
[0309] The NMP (44 mL) suspension of 2,2-dimethylmorpholine (Compound 7a, 1.98 g, 17.2 mmol),
tris (dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl
(0.123 g, 0.264 mmol), sodium tert-butoxide (5.08 g, 529 mmol) was de-aerated at room
temperature under reduced pressure, then, nitrogen was introduced in the vessel. Under
nitrogen atmosphere, Compound 6f (5.0 g, 13.2 mmol) obtained in Step 6-4 was added
to the suspension, and the mixture was stirred at 100°C for 0.5 h. then cooled to
room temperature. Formic acid was added to the mixture, and the resulting product
was directly purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic
acid) to obtain the titled Compound 7b (5.26 g, yield 96%).
[0310] LC/MS mass spectrometry: m/z 413 ([M+H]
+).
[0311] LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-1).
<Step 7-2>
3-[(1S,2S)-1-[5-(2,2-Dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 7c)
[0312] The titled compound was synthesized from Compound 7b obtained in Step 7-1 by performing
an operation similar to Step 1-10 of Example 1 using an appropriate reagent. The 2-oxoimidazole
reagent (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 8c) used in the synthesis of Example Compounds 8 to 10 was synthesized by
the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0045)
<Step 8-1>
1-1(1S,2S)-2-Methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic
acid (Compound 8b)
[0313] The N,N-dimethylacetamide (DMA) (2.64 mL) suspension of Compound 6f (0.30 g, 0.793
mmol) obtained in Step 6-4, palladium(II) acetate (35.6 mg, 0.159 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
(0.148 g, 0.317 mmol) was de-aerated under reduced pressure, then, nitrogen was introduced
in the vessel and the suspension was stirred at room temperature for 15 min. Under
nitrogen atmosphere, a DMA solution (7.9 mL, 7.93 mmol) of 1M (tetrahydro-2H-pyran-4-yl)zinc
(II) iodide (Compound 8a) was added, and the mixture was stirred at 80°C for 15 min.,
and then the mixture was cooled to room temperature. Formic acid was added to the
mixture, and the resulting product was directly purified by reversed-phase chromatography
(methanol/water) to obtain the titled Compound 8b (0.19 g, yield 61%).
[0314] LC/MS mass spectrometry: m/z 382 ([M-H]
-).
[0315] LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).
<Step 8-2>
3-1(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 8c)
[0316] The titled compound was synthesized from Compound 8b obtained in Step 8-1 by performing
an operation similar to Step 1-10 of Example 1 using an appropriate reagent.
[0317] The halogen compound (5-bromo-1-[(3R)-oxolan-3-yl]indazole, Compound 8f) used in
the synthesis of Example Compound 8 was synthesized by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0046)
<Step 8-3>
4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (Compound 8e)
[0318] To a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (Compound 8d, 500 mg,
5.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride
(1.51 g, 7.95 mmol) at 0°C. The solution was stirred at room temperature, then 15
h. later, water and 1N hydrochloric acid were added to separate out the organic layer.
The organic layer was washed sequentially with saturated sodium hydrogen carbonate
solution, and brine. The solvent was removed by evaporation under reduced pressure
to obtain the titled Compound 8e (1.36 g, yield 99%).
[0319] LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1).
[0320] 1H-NMR (400 MHz, CDCl
3) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H, m), 3.93-3.76 (4H, m),
2.46 (3H, s), 2.13-2.05 (2H, m).
<Step 8-4>
5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 8f)
[0321] To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg, 1.52 mmol)
was added cesium carbonate (992 mg, 3.05 mmol) and Compound 8e (369 mg, 1.52 mmol)
obtained in Step 8-3, and the mixture was stirred at 100°C for 2 h. After cooling
to room temperature, water was added to the reaction solution and extraction was performed
using ethyl acetate. The organic layer was washed with water, and the solvent was
removed by evaporation under reduced pressure. The resulting product was purified
by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain the titled
Compound 8f (198 mg, yield 49%) as a colorless oil-like product.
[0322] LC/MS mass spectrometry: m/z 267 ([M+H]
+).
[0323] LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-1).
[0324] The halogen compound (N-(4-bromo-2-methoxyphenyl)-N-(3-methoxypropyl) acetamide,
Compound 9c) used in the synthesis of Example Compound 9 was synthesized by the following
process.
<Step 9-1>
[0325]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0047)
[0326] To a DMF (0.8 mL) solution of N-(4-bromo-2-methoxyphenyl)acetamide (Compound 9a,
80 mg, 0.33 mmol) was sequentially added sodium hydride (50 wt% oil dispersion) (18.9
mg, 0.39 mmol) and 1-bromo-3-methoxypropane (75 mg, 0.49 mmol), and the resulting
mixture was stirred at room temperature for 12 h. Formic acid was added to the reaction
solution, and the resulting product was purified by reversed-phase silica gel chromatography
(acetonitrile/water, 0.1% formic acid) to obtain the titled Compound 9c (103 mg, yield
99%) as a colorless gum-like product.
[0327] LC/MS mass spectrometry: m/z 316 ([M+H]
+).
[0328] LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
[0329] The halogen compound (5-bromo-1- (2,2,2-trifluoroethyl)indazole, Compound 10b) used
in the synthesis of Example Compound 10 was synthesized by the following process.
<Step 10-1>
[0330]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0048)
[0331] The titled compound was synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonate
(Compound 10a) and 5-bromo-1H-indazole (Compound 6j) by performing an operation similar
to Step 8-4 of Example 8 using an appropriate reagent.
[0332] LC/MS mass spectrometry: m/z 279 ([M+H]
+).
[0333] LC/MS retention time: 1.17 min. (Analysis Condition: SMD-FA05-1).
[0334] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5-dimethylphenyl)-4-methyl-3-
(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 11m) used in the synthesis of Example Compounds 11 to 13 was synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0049)
<Step 11-1>
tert-Butyl N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate
(Compound 11b)
[0335] [0327] 5-Bromo-2-fluoro-1,3-dimethylbenzene (Compound 11a, 4.66 g, 22.6 mmol) was
dissolved in THF (47.6 mL) and cooled under an external temperature of -70°C. 1.55M
n-Butyl lithium (13.1 mL, 20.4 mmol) was added dropwise at a temperature of -70°C
or lower and stirred for 1 h. A toluene solution (25.0 g, 21.7 mmol) of 20 wt% di-tert-butyl
azodicarboxylate was added dropwise at an internal temperature of -40°C or lower,
and the mixture was stirred for 30 min. Then, the mixture was warmed to room temperature
over a period of 1 h., and heptane (23.8 mL) and 20% ammonium chloride solution (47.6
mL) were added to perform extraction. The organic layer was concentrated and heptane
(7.14 mL) was added to the concentrated organic layer, and the mixture was heated
to an external temperature of 70°C to promote dissolution. Then, the solution was
cooled over a period of 1 h. to induce the precipitation of crystals. The crystals
were collected by filtration and washed with heptane (2.38 mL). The crystals were
dried to obtain a crude product (3.53 g, yield 44%) of the titled Compound 11b.
[0336] 1H-NMR (400 MHz, DMSO-D
6) δ: 9.64-9.51 (0.8H, m), 9.24-9.07 (0.2H, m), 7.09-6.91 (2H, m), 2.29-2.09 (6H, m),
1.53-1.32 (18H, m).
[0337] LC/MS retention time: 1.40 min. (Analysis Condition: SMD-FA05-3).
<Steps 11-2, 3, and 4>
tert-Butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (Compound 11g)
[0338] (3S)-3-Aminobutanenitrile hydrochloride (Compound 11c, 10.0 g, 82.9 mmol) was dissolved
in ethanol (50.0 mL), and triethyl amine (13.9 mL, 99.5 mmol) and, to the mixture,
ethyl acrylate (10.8 mL, 99.5 mmol) were added at room temperature. The solution was
stirred at an external temperature of 70°C for 3 h., then cooled to room temperature
to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]propanoate
(Compound 11e). To the reaction solution was added di-tert-butyl dicarbonate (21.7
mL, 99.5 mmol) at room temperature. The solution was stirred at room temperature for
14 h., then N-methylpiperazine (2.76 mL, 24.9 mmol) was added and the mixture was
stirred for 4 h. Then, 1N hydrochloric acid (50 mL) was added and extraction was performed
using toluene (50 mL). The organic layer was washed with 15% sodium chloride aqueous
solution (50.0 mL). The organic layer was concentrated under reduced pressure to obtain
a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate
(Compound 11f).
[0339] To the mixture was added THF (50.0 mL), then potassium tert-butoxide (10.2 g, 91.2
mmol) was added at an internal temperature of 30°C or lower. Then, the mixture was
stirred at room temperature for 1 h. At an internal temperature of 15°C, 2N hydrochloric
acid (82.9 mL, 99.5 mmol) was added and extraction was performed using ethyl acetate.
The organic layer was concentrated after it was washed twice with 15% sodium chloride
aqueous solution (50.0 mL) to obtain the titled Compound 11g (15.8 g, yield 80%).
[0340] LC/MS mass spectrometry: m/z 237 ([M-H]
-).
[0341] LC/MS retention time: 0.92 min. (Analysis Condition: SMD-FA05-1).
<Step 11-5>
tert-Butyl (4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 11h)
[0342] Compound 11b (2.13 g, 6.01 mmol) obtained in Step 11-1 was dissolved in NMP (6.39
mL), to which methanesulfonic acid (1.30 g, 13.2 mmol) was added and the mixture was
stirred at an external temperature of 80°C for 7 h. After the reaction solution was
cooled to room temperature, toluene (12.8 mL), potassium carbonate (0.914 g), and
water (12.8 g) were added to it, and the reaction solution was stirred at room temperature
for 10 min. After removing the water layer, a toluene (6.3 mL) solution of Compound
11g (1.43 g, 6.01 mmol) obtained in Step 11-4, pyridine hydrochloride (71.0 mg, 0.60
mmol) and toluene (4.2 mL) were added and the reaction solution was stirred at an
external temperature of 90°C for 1 h. The reaction solution was cooled, then washed
with 1M sodium hydroxide aqueous solution (12.6 mL). The organic layer was concentrated
under reduced pressure to synthesize the titled Compound 11h (1.68 g, yield 75%).
[0343] LC/MS mass spectrometry: m/z 375 ([M+H]
+).
[0344] LC/MS retention time: 1.08 min. (Analysis Condition: SMD-FA05-1).
<Step 11-6>
tert-Butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2- (4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 11j)
[0345] To a DMA (0.53 mL) solution of Compound 11h (106 mg, 0.283 mmol) obtained in Step
11-5 was added N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (Compound 11i, 62.0 mg,
0.311 mol), then potassium tert-butoxide (95.0 mg, 0.849mol) was added under a nitrogen
atmosphere, and the mixture was stirred at an external temperature of 25°C for 4 h.
Water was added to the reaction solution and extraction was performed using ethyl
acetate. The organic layer was washed with water, and the solvent was removed by evaporation
under reduced pressure. The resulting product was purified by silica gel column chromatography
(ethyl acetate/hexane=3:2) to obtain the titled Compound 11j (105 mg, yield 73%).
[0346] LC/MS mass spectrometry: m/z 506 ([M+H]
+).
[0347] LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).
<Step 11-7>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3- (2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolol4,3-c1pyridine-5-carboxylate
Compound 11k)
[0348] Compound 11j (4.45 g, 8.79 mmol) obtained in Step 11-6 was suspended by adding THF
(44.5 mL), then methylsulfonic acid (0.676 g, 7.03 mmol) was added, and the resulting
mixture was stirred at an external temperature of 60°C for 2 h. After cooling to room
temperature, a solution of tripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8
mL) was added, di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) was added, and the resulting
mixture was stirred at room temperature for 1 h. Water was added to the reaction solution
and extraction was performed using ethyl acetate. The organic layer was washed with
a saturated sodium chloride aqueous solution, then dried using magnesium sulfate.
After filtration, the organic layer was concentrated under reduced pressure, and purified
by silica gel column chromatography (ethyl acetate/hexane=3:7) to obtain the titled
Compound 11k (3.43 g, yield 88%).
[0349] LC/MS mass spectrometry: m/z 442 ([M+H]
+).
[0350] LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).
<Step 11-8>
3-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one
hydrochloride (Compound 11l)
[0351] To a dichloromethane (8.38 ml) solution of Compound 11k (1.85 g, 4.19 mmol) obtained
in Step 11-7 was added a 4M hydrogen chloride dioxane solution (10.5 mL, 41.9 mmol).
The mixture was stirred at room temperature for 1h., and the reaction mixture was
concentrated under reduced pressure to obtain a crude product (1.63 g) containing
the titled Compound 11l as a brown solid.
[0352] LC/MS mass spectrometry: m/z 342 ([M+H]
+).
[0353] LC/MS retention time: 0.63 min. (Analysis Condition: SMD-FA05-1).
<Step 11-9>
3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolor4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 11m)
[0354] The titled compound was synthesized from Compound 11l obtained in Step 11-8 and Compound
6h obtained in Step 6-5 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0355] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 14d) used in the synthesis of Example Compound 14 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0050)
<Step 14-1>
5-(2-Chloro-3-fluoropyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl1indole-2-carboxylic
acid (Compound 14b)
[0356] The titled compound was synthesized from Compound 6f obtained in Step 6-4 and 2-chloro-3-fluoro-4-iodopyridine
(Compound 14a) by performing an operation similar to Step 6-5 of Example 6 using an
appropriate reagent.
[0357] LC/MS mass spectrometry: m/z 429 ([M+H]
+).
[0358] LC/MS retention time: 1.14 min. (Analysis Condition: SMD-TFA05-3).
<Step 14-2>
5-(3-Fluoro-2-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1- (5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 14c)
[0359] To a mixed suspension of DMSO/water at 7:1 (13.2 mL) containing Compound 14b (810
mg, 1.32 mmol) obtained in Step 14-1, 1,1'-bis (diphenylphosphino)ferrocenepalladium(II)
dichloride (48 mg, 0.066 mmol), potassium carbonate (2.74 g, 19.8 mmol), methylboronic
acid (792 mg, 13.2 mmol) was de-aerated under reduced pressure at room temperature,
then nitrogen was introduced in the vessel. Under a nitrogen atmosphere, the mixture
was stirred at 100°C for 0.5 h, then cooled to room temperature. Formic acid was added
to the mixture, which was directly purified by reversed-phase chromatography (acetonitrile/water,
0.1% formic acid) to obtain the titled Compound 14c (124 mg, yield 23%) as a pale
yellow solid.
[0360] LC/MS mass spectrometry: m/z 409 ([M+H]
+).
[0361] LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).
<Step 14-3>
3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 14d)
[0362] The titled compound was synthesized from Compound 11l obtained in Step 11-8 and Compound
14c obtained in Step 14-2 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0363] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[2- (dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-
(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 15d) used in the synthesis of Example Compound 15 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0051)
<Step 15-1>
4- Iodo-N,N,3-trimethylpyridine-2-amine (Compound 15b)
[0364] A DMF (7.9 mL) solution of 2-chloro-4-iodo-3-methylpyridine (Compound 15a, 500 mg,
1.97 mmol), N-ethyl-N-propan-2-ylpropane-2-amine (0.515 mL, 2.96 mmol), and a THF
solution (2.96 mL, 5.92 mmol) of 2M dimethylamine was stirred at 130°C for 17 h.,
then the solution was cooled to room temperature and formic acid (0.4 mL) was added.
The solution was purified by reversed-phase chromatography (acetonitrile/water, 0.1%
formic acid) to obtain the titled Compound 15b (258 mg, yield 50%) as a light brown
solution.
[0365] LC/MS mass spectrometry: m/z 263 ([M+H]
+).
[0366] LC/MS retention time: 0.52 min. (Analysis Condition: SQD-FA05-1).
<Step 15-2>
5-[2-(Dimethylamino)-3-methylpyridin-4-yl]-1-[(1S,2S)-2-methyl-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 15c)
[0367] The titled compound was obtained from Compound 6f obtained in Step 6-4 and Compound
15b obtained in Step 15-1 by performing an operation similar to Step 6-5 of Example
6 using an appropriate reagent.
[0368] LC/MS mass spectrometry: m/z 432 ([M-H]
-).
[0369] LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-1).
<Step 15-3>
3-[(1S,2S)-1-[5-[2-(Dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-
(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 15d)
[0370] The titled compound was synthesized from Compound 15c obtained in Step 15-2 and Compound
11l obtained in Step 11-8 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0371] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2- (4-fluoro-3,5-dimethylphenyl)-
4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 16a) used in the synthesis of Example Compounds 16 to 30 was synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0052)
<Step 16-1>
3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3- 2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 16a)
[0372] The titled compound was obtained from Compound 111 obtained in Step 11-8 and Compound
8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0373] The halogen compound (5-bromo-1-[(3-methyloxetan-3-yl)methyl]indazole, Compound 17b)
used in the synthesis of Example Compound 17 was synthesized by the following process.
<Step 17-1>
[0374]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0053)
[0375] The titled compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane
(Compound 17a) and 5-bromo-1H-indazole (Compound 6j) by performing an operation similar
to Step 9-1 of Example 9 using an appropriate reagent.
[0376] LC/MS mass spectrometry: m/z 281 ([M+H]
+).
[0377] LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).
[0378] The halogen compound (2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol, Compound
20b) used in the synthesis of Example Compound 20 was synthesized by the following
process.
<Step 20-1>
2-(4-Bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (Compound 20b)
[0379]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0054)
[0380] Under a nitrogen atmosphere, a THF solution (0.95M, 4.37 mL, 4.15 mmol) of borane
was added dropwise at 0°C to a THF solution (1.38 mL) of 2-(4-bromo-2-methoxyphenoxy)-2-methylpropane
carboxylic acid (Compound 20a, 400 mg, 1.38 mmol) and the resulting mixture was stirred
for 24 h. After 1M sodium hydroxide aqueous solution was added to the mixture and
the mixture was stirred, 1N hydrochloric acid was added for neutralization. Then,
ethyl acetate was added to perform extraction. The organic layer was washed with water
and the solvent was removed by evaporation under reduced pressure to obtain the titled
Compound 20b (339 mg, yield 89%).
[0381] LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).
[0382] 1H-NMR (400 MHz, CDCl
3) δ: 7.04-7.01 (2H, m), 6.90-6.86 (1H, m), 3.85 (3H, s), 3.44 (2H, m), 3.34 (1H, m),
1.28 (6H, s).
[0383] The halogen compound (5-bromo-1-[(3S)-oxolan-3-yl]indazole, Compound 22c) used in
the synthesis of Example Compound 22 was synthesized by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0055)
<Step 22-1>
(3R)-Oxolan-3-yl 4-methylbenzenesulfonate (Compound 22b)
[0384] The titled compound was synthesized by performing an operation similar to Step 8-3
of Example 8 using (3R)-oxolan-3-ol and an appropriate reagent.
[0385] LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-3).
<Step 22-2>
5-Bromo-1-[(3S)-oxolan-3-yl]indazole (Compound 22c)
[0386] The titled compound was synthesized from Compound 22b obtained in Step 22-1 and 5-bromo-1H-indazole
by performing an operation similar to Step 8-4 of Example 8 using an appropriate reagent.
[0387] LC/MS mass spectrometry: m/z 267 ([M+H]
+).
[0388] LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).
[0389] The halogen compound (6-bromo-1,1-dimethyl-3,4-dihydroisochromene, Compound 24d)
used in the synthesis of Example Compound 24 was synthesized by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0056)
<Step 24-1>
(1,1-Dimethyl-3,4-dihydroisochromen-6-yl) trifluoromethanesulfonate (Compound 24b)
[0390] The titled compound was synthesized from 1,1-dimethyl-3,4-dihydroisochromen-6-ol
(Compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride)
by performing an operation similar to Step 8-3 of Example 8 using an appropriate reagent.
[0391] LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-01).
<Step 24-2>
2-(1,1-Dimethyl-3,4-dihydroisochromen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Compound 24c)
[0392] After the 1,4-dioxane (2.58 mL) solution of Compound 24b (120 mg, 0.387 mmol) obtained
in Step 24-1, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane
(147 mg, 0.580 mmol), triethyl amine (0.162 mL, 1.16 mmol), [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II)
(14.2 mg, 0.019 mmol) was de-aerated under reduced pressure, nitrogen was introduced
in the vessel and the solution was stirred at 100°C for 14 h. The solution was cooled
to room temperature, then formic acid was added and the resulting product was purified
by reversed-phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain
a mixture (134 mg) containing the titled Compound 24c as a light brown liquid.
[0393] LC/MS mass spectrometry: m/z 289 ([M+H]
+).
[0394] LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-1).
<Step 24-3>
6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (Compound 24d)
[0395] To a methanol (1.9 mL) solution of Compound 24c (111 mg, 0.385 mmol) obtained in
Step 24-2, an aqueous solution (1.9 mL) of copper(II) bromide (258 mg, 1.16 mmol)
was added and the mixture was stirred at 60°C for 6 h. After the mixture was cooled
to room temperature, a saturated ammonium chloride solution was added, then extraction
using dichloromethane was performed twice, and then the organic layer was dried with
magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure
and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:4)
to obtain the titled Compound 24d (47.7 mg, yield 51%) as a colorless liquid.
[0396] 1H-NMR (400 MHz, CDCl
3) δ: 7.29 (1H, dd, J=2.0, 8.4 Hz), 7.24-7.22 (1H, m), 6.97 (1H, d, J=8.4 Hz), 3.92
(2H, t, J=5.6 Hz), 2.80 (2H, t, J=5.6 Hz), 1.50 (6H, s).
[0397] LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-1).
[0398] The halogen compound (6-(4-bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine,
Compound 25b) used in the synthesis of Example Compound 25 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0057)
<Step 25-1>
6-(4-Bromo-2-methylphenyl)-N,N-dimethylpyrimidine-4-amine (Compound 25b)
[0399] To a methanol (0.2 mL) solution of 4-(4-bromo-2-methylphenyl)-6-chloropyrimidine
(Compound 25a, 12.9 mg, 0.045 mmol) was added 2M dimethylamine THF solution (0.227
mL, 0.455 mmol), and the mixture was stirred at room temperature for 3 h. The reaction
mixture was purified by the reversed-phase silica gel column chromatography (acetonitrile/water,
0.1% formic acid) to synthesize the titled Compound 25b (9.2 mg, yield 69%) as an
off-white solid.
[0400] LC/MS mass spectrometry: m/z 292 ([M+H]
+).
[0401] LC/MS retention time: 0.67 min. (Analysis Condition: SMD-FA05-3).
[0402] The halogen compound (5-bromo-4-fluoro-1- (2,2,2-trifluoroethyl)indazole, Compound
28b) used in the synthesis of Example Compound 28 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0058)
<Step 28-1>
5-Bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole (Compound 28b)
[0403] The titled compound was synthesized from 2,2,2-trifluoroethyl trifluoromethanesulfonate
(Compound 10a) and 5-bromo-4-fluoro-1H-indazole (Compound 28a) by performing an operation
similar to Step 8-4 of Example 8 using an appropriate reagent.
[0404] LC/MS mass spectrometry: m/z 297 ([M+H]
+).
[0405] LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).
[0406] The halogen compound (5-bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole, Compound
29a) used in the synthesis of Example Compound 29 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0059)
<Step 29-1>
5-Bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole (Compound 29a)
[0407] The titled compound was synthesized from 3-methyl-3-[(4-methylphenyl)sulfonylmethyl]oxetane
(Compound 17a) and 5-bromo-4-fluoro-1H-indazole (Compound 28a) by performing an operation
similar to Step 8-4 of Example 8 using an appropriate reagent.
[0408] LC/MS mass spectrometry: m/z 299 ([M+H]
+).
[0409] LC/MS retention time: 1.11 min. (Analysis Condition: SMD-FA05-1).
[0410] The halogen compound (1-(5-bromo-4-fluoroindazol-1-yl)-2-methylpropan-2-ol, Compound
30a) used in the synthesis of Example Compound 30 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0060)
<Step 30-1>
1-(5-Bromo-4-fluoroindazol-1-yl)-2-methylpropan-2-ol (Compound 30a)
[0411] The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole (Compound 28a)
and 2,2-dimethyloxirane (Compound 6k) by performing an operation similar to Step 6-7
of Example 6 using an appropriate reagent.
[0412] LC/MS mass spectrometry: m/z 287 ([M+H]
+).
[0413] LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-1).
[0414] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,
5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 311) used in the synthesis of Example Compounds 31 to 40 was synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0061)
<Step 31-1>
Ethyl 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate (Compound 31c)
[0415] Zinc powder (1.95 g, 29.8 mmol) was suspended in DMF (6 mL), and the suspension was
subjected to nitrogen substitution. Chlorotrimethylsilane (0.417 mL, 3.28 mmol), and
1,2-dibromoethane (0.284 mL, 3.28 mmol) were added and the resulting mixture was stirred
at room temperature for 5 min. A DMF (9 mL) solution of 4-iodo-2,2-dimethyltetrahydropyran
(5.37 g, 22.4 mmol) was added dropwise to the mixture, and the mixture was stirred
at room temperature for 20 min. To this solution were added palladium(II) acetate
(0.084 g, 0.373 mmol), and 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198
g, 0.746mol), ethyl 5-bromoindole-2-carboxylate (2.0 g, 7.46 mmol), and nitrogen was
introduced in the vessel. The mixture was stirred at an external temperature of 50°C
for 1 h., then the external temperature was cooled to 0°C, and 5N hydrochloric acid
(6 mL) was added for neutralization. A 30% sodium chloride aqueous solution (50 mL)
and ethyl acetate (100 mL) were added and the non-dissolved matters were removed with
cerite. The filtrate was subjected to extraction using ethyl acetate and the organic
layer was washed with 30% sodium chloride aqueous solution. Then, it was dried with
magnesium sulfate and run through a filter, and the solvent was removed by evaporation
under reduced pressure. The residue was purified by silica gel column chromatography
(ethyl acetate/hexane) to synthesize the titled Compound 31c (1.86 g, yield 83%) as
a pale pink solid.
[0416] LC/MS mass spectrometry: m/z 302 ([M+H]
+).
[0417] LC/MS retention time: 0.90 min. (Analysis Condition: SQD-FA05-4).
<Step 31-2>
Ethyl 5-[(4S)-22-dimethyloxan-4-yl]-1H-indole-2-carboxylate (Compound 31d)
[0418] The stereoisomers included in Compound 31c (900 mg) obtained by Step 31-1 were separated
by supercritical-fluid chromatography to obtain the titled Compound 31d (423 mg, yield
47%).
Separation condition
[0419]
Device: SFC15 (Waters)
Column: CHIRALPAK-IE/SFC, 10×250 mm, 5 µm (Daicel)
Column temperature: 40°C
Solvent: Super-critical carbon dioxide/methanol: ethyl acetate (1:1)=60/40
(Homogenous system)
[0420]
Flow rate: 15 mL/min., 140 bar
Analysis Condition
Device: Nexera (Shimadzu)
Column: CHIRALPAK-IE, 4.6×250 mm, 5 µm (Daicel)
Column Temperature: 25°C
Solvent: hexane/ethanol=30/70 (homogenous system)
Flow rate: 1 mL/min., room temperature
Titled Compound retention time: 9.98 min., isomer retention time: 6.86 min.
[0421] Note that the titled compound was determined to be the S-isomer by X-ray crystallography
of Compound 31j.
<Step 31-3>
5-[(4S)-2,2-Dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (Compound 31e)
[0422] Compound 31d (993 mg, 3.29 mmol) obtained in Step 31-2 was dissolved in methanol
(14.9 mL), and a 2M sodium hydroxide aqueous solution (3.62 mL, 7.25 mmol) was added
dropwise into the mixture and the mixture was stirred at an external temperature of
65°C for 1 h. The reaction solution was cooled at an external temperature of 15°C,
and 5N hydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise into the reaction
solution. Water (7.45 mL) was added dropwise, and the precipitated solid was collected
by filtration. The obtained solid was washed with water (5.0 mL) and dried under reduced
pressure to obtain the titled Compound 31e (827 mg, yield 96%).
[0423] LC/MS mass spectrometry: m/z 274 ([M+H]
+).
[0424] LC/MS retention time: 0.65 min. (Analysis Condition: SQD-FA05-4).
<Step 31-4>
5-[(4S)-2,2-Dimethyloxan-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound
31f)
[0425] Compound 31e (805 mg, 2.95 mmol) obtained in Step 31-3 was dissolved in DMA (8.0
mL), and thionyl chloride (0.256 mL, 3.53 mmol) was added dropwise into the solution
at an internal temperature of 10°C or lower. After the solution was stirred for an
hour, N-methylaniline (0.384 mL, 3.53 mmol) and triethyl amine (0.985 mL, 7.07 mmol)
were added dropwise at 10°C or lower, and the solution was stirred at room temperature
for 1 h. Water (4.0 mL) was added dropwise into the solution, and the precipitated
solid was collected by filtration. The obtained solid was washed with water (8.0 mL)
and dried under reduced pressure to obtain the titled Compound 31f (995 mg, yield
93%).
[0426] LC/MS mass spectrometry: m/z 363 ([M+H]
+).
[0427] LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).
<Step 31-5>
1-(Cyanomethyl)-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide
(Compound 31h)
[0428] Compound 31f (101 mg, 0.276 mmol) obtained in Step 31-4 was dissolved in 1,3-dimethyl-2-imidazolidinone
(DMI) (1.0 mL) at room temperature, and 8M potassium hydroxide aqueous solution (0.103
mL, 0.828 mmol) and water (0.10 mL) were added to the solution. To the obtained solution
was added 2-chloroacetonitrile (0.026 mL, 0.414 mmol) at an external temperature of
10°C, and the solution was stirred for 2.5 h. 5N Hydrochloric acid (0.193 mL), water
(0.10 mL), and cyclopentylmethyl ether (1.0 mL) were added to the reaction solution
to perform extraction, and the aqueous layer was subjected to a second extraction
using cyclopentylmethyl ether (1.0 mL). The combined organic layer was washed with
15% sodium chloride solution (1.0 mL), then, the titled Compound 31h was obtained
as a light brown oil-like product by concentration under a reduced pressure at an
external temperature of 40°C and was put to use in the subsequent Step 31-6 without
being purified.
[0429] LC/MS mass spectrometry: m/z 402 ([M+H]
+).
[0430] LC/MS retention time: 0.93 min. (Analysis Condition: SMD-FA05-1).
<Step 31-6>
1-[(1S,2S)-1-Cyano-2-methylcyclopropyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide
(Compound 31i)
[0431] The titled compound was synthesized from Compound 31h obtained in Step 31-5 by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0432] LC/MS mass spectrometry: m/z 442 ([M+H]
+).
[0433] LC/MS retention time: 0.95 min. (Analysis Condition: SQD-FA05-1).
<Step 31-7>
5-[(4S)-2,2-Dimethyloxan-4-yl]-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide
(Compound 31j)
[0434] The titled compound was synthesized from Compound 31i obtained in Step 31-6 by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0435] LC/MS mass spectrometry: m/z 501 ([M+H]
+).
[0436] LC/MS retention time: 0.99 min. (Analysis Condition: SQD-FA05-1).
<Step 31-8>
5-[(4S)-2,2-Dimethyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 31k)
[0437] The titled compound was synthesized from Compound 31j obtained in Step 31-7 by performing
an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
[0438] LC/MS mass spectrometry: m/z 401 ([M-H]
-).
[0439] LC/MS retention time: 1.05 min. (Analysis Condition: SMD-FA05-1).
<Step 31-9>
3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 311)
[0440] The titled compound was synthesized from Compound 111 obtained in Step 11-8 and Compound
31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0441] The halogen compound 5-bromo-1-(2-methoxyethyl)-3-methylbenzoimidazol-2-one (Compound
33b) used in the synthesis of Example Compound 33 was synthesized by the following
process.
<Step 33-1>
[0442]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0062)
[0443] The titled compound was synthesized from 5-bromo-3-methyl-1H-benzoimidazol-2-one
(Compound 33a) by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
[0444] LC/MS mass spectrometry: m/z 285 ([M+H]
+).
[0445] LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-1).
[0446] The halogen compound (5-bromo-4-fluoro-1- (2-methoxyethyl)indazole, Compound 36a)
used in the synthesis of Example Compound 36 was synthesized by the following process.
<Step 36-1>
[0447]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0063)
[0448] The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole (Compound 28a)
by performing an operation similar to Step 8-4 of Example 8 using an appropriate reagent.
[0449] LC/MS mass spectrometry: m/z 273 ([M+H]
+).
[0450] LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
[0451] The halogen compound (5-bromo-4-fluoro-1-[(3S)-oxolan-3-yl]indazole, Compound 40a)
used in the synthesis of Example Compound 40 was synthesized by the following process.
<Step 40-1>
[0452]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0064)
[0453] The titled compound was synthesized from 5-bromo-4-fluoro-1H-indazole (Compound 28a)
and (3R)-oxolan-3-yl 4-methylbenzenesulfonate (Compound 22b) by performing an operation
similar to Step 8-4 of Example 8 using an appropriate reagent.
[0454] LC/MS mass spectrometry: m/z 285 ([M+H]
+).
[0455] LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
[0456] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 41f) used in the synthesis of Example Compound 41 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0065)
<Steps 41-1 and 2>
1-[(1S,2S)-1-Cyano-2-methylcyclopropyl]-N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-N-phenylindole-2-carboxamide
(Compound 41c)
[0457] After a DMA (0.12 mL) suspension of zinc (29 mg, 0.44 mmol) was de-aerated under
at room temperature at room temperature, nitrogen was introduced in the vessel. Under
a nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane/1,2-dibromoethane
(0.0083 mL, 0.039 mmol of chlorotrimethylsilane) was added, and the mixture was stirred
for 15 min., then (2S)-4-iodo-2-methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added
dropwise at room temperature and the mixture was stirred for 30 min. to obtain a mixture
containing iodo-[(2S)-2-methyloxan-4-yl]zinc (Compound 41b). Palladium(II) acetate
(6.4 mg, 0.028 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (26 mg, 0.057
mmol), 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide
(58 mg, 0.14 mmol), and DMA (0.123 mL) were added, and the mixture was de-aerated
under reduced pressure, then nitrogen was introduced in the vessel and the mixture
was stirred for an hour at 80°C. The mixture was cooled to room temperature, to which
ethyl acetate and 1N hydrochloric acid were added, and the mixture was filtered. Then,
the filtrate was subjected to extraction using ethyl acetate. The organic layer was
washed once with brine and concentrated under reduced pressure, then, the residue
was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain
the titled Compound 41c (31 mg, yield 51%).
[0458] LC/MS mass spectrometry: m/z 428 ([M+H]
+).
[0459] LC/MS retention time: 1.01 min. (Analysis Condition: SQD-AA05-1).
<Step 41-3>
N-Methyl-5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1- (5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide
(Compound 41d)
[0460] The titled compound was synthesized from Compound 41c obtained in Step 41-2 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0461] LC/MS mass spectrometry: m/z 487 ([M+H]
+).
[0462] LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 41-4>
5-[(2S,4S)-2-Methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 41e)
[0463] The titled compound was synthesized from Compound 41d obtained in Step 41-3 by performing
an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
[0464] LC/MS mass spectrometry: m/z 396 ([M-H]
-).
[0465] LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
<Step 41-5>
3-[(1S,2S)-1-[2-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 41f)
[0466] The titled compound was synthesized from Compound 41e obtained in Step 41-4 by performing
an operation similar to Step 1-10 of Example 1 using an appropriate reagent. The 2-oxoimidazole
reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 42g) used in the synthesis of Example Compounds 42 and 43 were synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0066)
<Steps 42-1, 2>
tert-Butyl (4S)-3-amino-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 42c)
[0467] After (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 42b) was obtained
from 4-chloro-3,5-dimethylaniline (Compound 42a) by performing an operation similar
to Step 2-2 of Example 2 using an appropriate reagent, Compound 11g obtained in Step
11-4 and an appropriate reagent were used to synthesize Compound 42c by an operation
similar to Step 1-2 of Example 1.
[0468] LC/MS mass spectrometry: m/z 391 ([M+H]
+).
[0469] LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA10-4).
<Step 42-3>
tert-Butyl (4S)-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 42d)
[0470] The titled compound was synthesized from Compound 42c obtained in Step 42-2 by performing
an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
[0471] LC/MS mass spectrometry: m/z 522 ([M+H]
+).
[0472] LC/MS retention time: 1.55 min. (Analysis Condition: SMD-TFA05-5).
<Step 42-4>
tert-Butyl (4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3- (2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 42e)
[0473] The titled compound was synthesized from Compound 42d obtained in Step 42-3 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0474] LC/MS mass spectrometry: m/z 458 ([M+H]
+).
[0475] LC/MS retention time: 1.16 min. (Analysis Condition: SMD-FA05-1).
<Step 42-5>
3-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one
hydrochloride (Compound 42f)
[0476] The titled compound was synthesized from Compound 42e obtained in Step 42-4 by performing
an operation similar to Step 111-8 of Example 11 using an appropriate reagent.
[0477] LC/MS mass spectrometry: m/z 358 ([M+H]
+).
[0478] LC/MS retention time: 0.69 min. (Analysis Condition: SMD-FA05-1).
<Step 42-6>
3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 42g)
[0479] The titled compound was synthesized from Compound 42f obtained in Step 42-5 and Compound
31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0480] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2- (4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 44a) used in the synthesis of Example Compounds 44 and 45 were synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0067)
<Step 44-1>
3-[(1S,2S)-1-[2-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-
(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 44a)
[0481] The titled compound was synthesized from Compound 42f obtained in Step 42-5 and Compound
8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0482] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-
(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, Compound 46f)
used in the synthesis of Example Compounds 46 and 47 was synthesized by the following
process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0068)
<Step 46-1>
tert-Butyl (4S)-3-amino-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 46b)
[0483] The titled compound was synthesized from (4-fluoro-3-methylphenyl)hydrazine hydrochloride
(Compound 46a) and Compound 11g obtained in Step 11-4 by performing an operation similar
to Step 1-2 of Example 1 using an appropriate reagent.
[0484] LC/MS mass spectrometry: m/z 361 ([M+H]
+).
[0485] LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
<Step 46-2>
tert-Butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 46c)
[0486] The titled compound was synthesized from Compound 46b obtained in Step 46-1 by performing
an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
[0487] LC/MS mass spectrometry: m/z 492 ([M+H]
+).
[0488] LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-1).
<Step 46-3>
tert-Butyl (4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolor4,3-c]pyridine-5-carboxylate
Compound 46d)
[0489] The titled compound was synthesized from Compound 46c obtained in Step 46-2 by performing
an operation similar to Step 11-7 of Example 11 using an appropriate reagent.
[0490] LC/MS mass spectrometry: m/z 428 ([M+H]
+).
[0491] LC/MS retention time: 2.11 min. (Analysis Condition: SMD-FA05-long).
<Step 46-4>
3-[(4S)-2-(4-Fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one
hydrochloride (Compound 46e)
[0492] The titled compound was synthesized from Compound 46d obtained in Step 46-3 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0493] LC/MS mass spectrometry: m/z 328 ([M+H]
+).
[0494] LC/MS retention time: 0.59 min. (Analysis Condition: SMD-FA05-3).
<Step 46-5>
3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolor4,3-c]pyridine-5-carbonyl]-5-
(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Compound 46f)
[0495] The titled compound was synthesized from Compound 46e obtained in Step 46-4 and Compound
8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0496] The 2-oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one,
Compound 48a) used in the synthesis of Example Compounds 48 to 50 was synthesized
by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0069)
<Step 48-1>
3-1(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2- (4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 48a)
[0497] The titled compound was synthesized from Compound 46e obtained in Step 46-5 and Compound
31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
<Examples 51 to 53>
[0498] An operation similar to Step 7-1 of Example 7 was performed using 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 51d), substituted morpholine and an appropriate reagent to obtain Example
Compounds 51 to 53 shown in Table 2-4 by the following reaction.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0071)
[0499] Compound 51d was synthesized as follows.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0073)
<Step 51-1>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
Compound 51a)
[0500] [0426] To a dichloromethane (16.8 mL) suspension of Compound 2f (0.611 g, 1.68 mmol)
obtained in Step 2-5 was added triethyl amine (0.936 mL, 6.72 mmol), di-tert-butyl
dicarbonate (0.425 mL, 1.85 mmol), and the suspension was stirred at room temperature
for 2 h. Water (20.0 mL) and 5% potassium hydrogen sulfate aqueous solution (20.0
mL) were added to the reaction solution, then extraction was performed using dichloromethane,
and the resulting product was dried using magnesium sulfate. After filtration, the
filtrate was concentrated under reduced pressure and the residue was purified by silica
gel column chromatography (ethyl acetate/hexane=0:1 to 1:0) to obtain the titled Compound
51a (0.360 g, yield 50%).
[0501] LC/MS mass spectrometry: m/z 428 ([M+H]
+).
[0502] LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).
<Step 51-2>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 51b)
[0503] [0427] The titled compound was synthesized from Compound 51a obtained in Step 51-1
and 5-bromo-1-methylindazole by performing an operation similar to Step 1-11 of Example
1 using an appropriate reagent.
[0504] LC/MS mass spectrometry: m/z 558 ([M+H]
+).
[0505] LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).
<Step 51-3>
1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 51c)
[0506] [0428] The titled compound was synthesized from Compound 51b obtained in Step 51-2
by performing an operation similar to Step 11-9 of Example 11 using an appropriate
reagent.
[0507] LC/MS mass spectrometry: m/z 458 ([M+H]
+).
[0508] LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1).
<Step 51-4>
3-[(1S,2S)-1-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 51d)
[0509] [0429] The titled compound was synthesized from Compound 51c obtained in Step 51-3
and Compound 6f obtained in Step 6-4 by performing an operation similar to Step 1-10
of Example 1 using an appropriate reagent.
[0510] LC/MS mass spectrometry: m/z 817 ([M+H]
+).
[0511] LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).
<Examples 54 to 73>
[0513] Note that the compounds in Table 2-5 have rotational isomers, and by way of example,
the
1H-NMR of Example Compounds 66 and 67 are shown below.
<Example Compound 66>
Main rotational isomer
[0514] 1H-NMR (600MHz, CDCl
3) δ: 11.32 (1H, s), 8.04 (1H, d, J=0.4 Hz), 7.86 (1H, d, J=1.4 Hz), 7.61 (1H, m),
7.59 (1H, m), 7.52 (1H, s), 7.50 (H, d, J=9.0 Hz), 7.27 (1H, m), 7.15 (2H, d, J
HF=6.0 Hz), 6.74 (1H, d, J=3.1 Hz), 6.70 (1H, s), 6.32 (1H, d, J=3.1 Hz), 5.79 (1H,
q, J=6.6 Hz), 4.47 (1H, dd, J=13.6, 5.0 Hz), 4.12 (3H, s), 3.89-3.81 (2H, m), 3.60
(1H, ddd, J=13.6, 13.1, 3.6 Hz), 3.15 (1H, ddd, J=16.0, 13.1, 5.0 Hz), 3.09-2.98 (2H,
m), 2.27 (6H, d, J
HF=1.4 Hz), 1.91 (1H, dd, J=6.0 Hz), 1.82-1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H,
d, J=6.6 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.19 (3H, d, J=5.9 Hz).
Secondary rotational isomer
[0515] 1H-NMR (600 MHz, CDCl
3) δ: 11.26 (1H, s), 7.93 (1H, s), 7.65 (1H, s), 7.57 (1H, d, J=8.6 Hz), 7.49 (1H,
m), 7.34 (2H, s), 7.25 (1H, m), 7.05 (2H, d, J
HF=6.0 Hz), 6.69 (1H, s), 6.59 (1H, d, J=3.1 Hz), 6.09 (1H, d, J=3.1 Hz), 5.26 (1H,
q, J=6.6 Hz), 4.87 (1H, dd, J=12.8, 5.1 Hz), 4.07 (3H, s), 3.90-3.78 (2H, m), 3.40
(1H, ddd, J=12.8, 12.6, 4.5 Hz), 3.10-2.98 (3H, m), 2.23 (6H, s), 1.82-1.37 (10H,
m), 1.33 (3H, s), 1.25 (3H, s), 1.06 (3H, d, J=6.2 Hz).
<Example Compound 67>
Main rotational isomer
[0516] 1H-NMR (600 MHz, CDCl
3) δ: 11.32 (1H, s), 8.13 (1H, d, J
HF=0.7 Hz), 7.59 (1H, d, J=8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J=8.9 Hz, J
HF=6.9 Hz), 7.28 (1H, d, J=8.9 Hz), 7.26 (1H, dd, J=8.6, 1.7 Hz), 7.16 (2H, d, J
HF=6.1 Hz), 6.70 (1H, s), 6.61 (1H, dd, J=3.0 Hz, J
HF=1.1 Hz), 6.31 (1H, d, J=3.0 Hz), 5.79 (1H, q, J=6.7 Hz), 4.47 (1H, dd, J=13.5, 5.2
Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1H, m), 3.60 (1H, ddd, J=13.5, 12.9, 3.6 Hz),
3.15 (1H, ddd, J=15.8, 12.9, 5.2 Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J
HF=1.1 Hz), 1.91 (1H, dd, J=6.1, 5.8 Hz), 1.79-1.76 (2H, m), 1.74 (1H, m), 1.65 (1H,
m), 1.57 (3H, d, J=6.7 Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8 Hz), 1.34
(3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0 Hz). Secondary rotational isomer
[0517] 1H-NMR (600 MHz, CDCl
3) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J=8.7 Hz), 7.52 (1H, s), 7.25-7.22
(2H, m), 7.12 (1H, d, J=8.8 Hz), 7.06 (2H, d, J
HF=6.0 Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 (1H, d, J=3.0 Hz), 5.26 (1H, q, J=6.6 Hz),
4.87 (1H, dd, J=13.1, 4.8 Hz), 4.07 (3H, s), 3.90-3.80 (2H, m), 3.39 (1H, ddd, J=13.1,
12.2, 4.6 Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6
Hz), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 (3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0
Hz).
[0518] Compound 55e used in the synthesis of Example Compound 55 was synthesized as follows.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0081)
<Step 55-1>
tert-Butyl 3-amino-2- (4-chloro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-clpyridine-5-carboxylate
(Compound 55a)
[0519] The titled compound was synthesized from Compound 42a obtained in Step 42-1 and Compound
1b obtained in Step 1-1 by performing an operation similar to Step 1-2 of Example
1 using an appropriate reagent.
[0520] LC/MS mass spectrometry: m/z 377 ([M+H]
+).
[0521] LC/MS retention time: 0.87 min. (Analysis Condition: SQD-FA05-1).
<Step 55-2>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3- (2,2-dimethoxyethylcarbamoylamino)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 55b)
[0522] The titled compound was synthesized from Compound 55a obtained in Step 55-1 by performing
an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
[0523] LC/MS mass spectrometry: m/z 508 ([M+H]
+).
[0524] LC/MS retention time: 0.83 min. (Analysis Condition: SQD-FA05-1).
<Step 55-3>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 55c)
[0525] The DMF (7.11 mL) suspension of Compound 55b (903 mg, 1.78 mmol) obtained in Step
55-2 and p-toluenesulfonic acid monohydrate (338 mg, 1.78 mmol) was stirred at 80°C
for 1 h. After the suspension was cooled to room temperature, potassium phosphate
(377 mg, 1.78 mmol), water (3.5 mL), and di-tert-butyl dicarbonate (388 mg, 1.78 mmol)
were added and the resulting mixture was stirred at room temperature for 1 h. Water
was added to the reaction mixture, and extraction was performed using ethyl acetate,
then the organic layer was washed with brine and the resulting product was dried with
magnesium sulfate anhydride. After filtration, the filtrate was concentrated under
reduced pressure and the residue was purified by silica gel column chromatography
(ethyl acetate/hexane=1:4 to 1:0) to obtain the titled Compound 55c (799 mg, yield
100%) as a pale yellow foam.
[0526] LC/MS mass spectrometry: m/z 444 ([M+H]
+).
[0527] LC/MS retention time: 0.82 min. (Analysis Condition: SQD-FA05-1).
<Step 55-4>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)-3-[3- (1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 55d)
[0528] The titled compound was synthesized from Compound 55c obtained in Step 55-3 and 5-bromo-1-methylindazole
(Compound 1q) by performing an operation similar to Step 1-11 of Example 1 using an
appropriate reagent.
[0529] LC/MS mass spectrometry: m/z 574 ([M+H]
+).
[0530] LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).
<Step 55-5>
1-[2-(4-Chloro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 55e)
[0531] The titled compound was synthesized from Compound 55d obtained in Step 55-4 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0532] LC/MS mass spectrometry: m/z 474 ([M+H]
+).
[0533] LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).
[0534] Compound 56c used in the synthesis of Example Compound 56 was synthesized as follows.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0082)
<Step 56-1>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1- (2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 56b)
[0535] The titled compound was synthesized from Compound 51a obtained in Step 51-1 and 5-bromo-1-
(2-methoxyethyl)indazole (Compound 56a) by performing an operation similar to Step
1-11 of Example 1 using an appropriate reagent.
[0536] LC/MS mass spectrometry: m/z 602 ([M+H]
+).
[0537] LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-2).
<Step 56-2>
1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one
hydrochloride (Compound 56c)
[0538] The titled compound was synthesized from Compound 56b obtained in Step 56-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0539] LC/MS mass spectrometry: m/z 502 ([M+H]
+).
[0540] LC/MS retention time: 0.54 min. (Analysis Condition: SQD-FA05-1).
[0541] The amine derivative (Compound 57j) used in the synthesis of Example Compound 57
was synthesized as follows.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0083)
<Step 57-1>
tert-Butyl N-(4-isocyanatocuban-1-yl) carbamate (Compound 57b)
[0542] To a toluene (2.1 mL) solution of 4-[(2-methylpropan-2-yl)oxycarbonylamino]cubane-1-carboxylic
acid (Compound 57a, 111 mg, 0.423 mmol) was added at room temperature triethyl amine
(0.0676 mL, 0.487 mmol) and diphenylphosphoryl azide (0.10 mL, 0.465 mmol), and the
resulting mixture was stirred at room temperature for 100 min., then at 85°C for 3.5
h. The solvent in the reaction mixture was removed by evaporation under reduced pressure,
and the titled Compound 57b was obtained as a crude product.
[0543] 1H-NMR (400 MHz, CDCl
3) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s).
<Step 57-2>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[[4-[(2-methylpropan-2-yl)oxycarbonylamino
lcuban-1-yllcarbamoylamino 1-6, 7-dihydro-4H-pyrazolor 43-c 1pyridine-5-carboxylate
(Compound 57c)
[0544] The titled compound was synthesized from Compound 57b obtained in Step 57-1 and Compound
11h obtained by Step 11-5 by performing an operation similar to Step 1-3 of Example
1 using an appropriate reagent.
[0545] LC/MS mass spectrometry: m/z 636 ([M+H]
+).
[0546] LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).
<Step 57-3>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[5-hydroxy3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]-2-oxoimidazolidin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 57d)
[0547] To a DMA (0.25 mL) suspension of Compound 57c (31.6 mg, 0.050 mmol) obtained in Step
57-2 and cesium carbonate (82.8 mg, 0.254 mmol) were added at room temperature 1,2-dichloro-1-ethoxyethane
(0.0155 mL, 0.127 mmol), and the mixture was stirred at room temperature for 170 min.
Cesium carbonate (104 mg, 0.32 mmol) followed by 1,2-dichloro-1-ethoxyethane (0.0184
mL, 0.162 mmol) were added to the reaction mixture at room temperature, and the resulting
mixture was stirred at room temperature for 16 h. The reaction mixture was diluted
with ethyl acetate and water, then 1N hydrochloric acid (0.54 mL) was added to adjust
the pH to 7, and then extraction was performed using ethyl acetate. The organic layer
was dried using magnesium sulfate, then the solvent was removed by evaporation under
reduced pressure, and then toluene was added and the solvent was removed by evaporation
under reduced pressure to obtain the titled Compound 57d as a crude product.
[0548] LC/MS mass spectrometry: m/z 678 ([M+H]
+).
[0549] LC/MS retention time: 0.98 min. (Analysis Condition: SQD-FA05-1).
<Step 57-4>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-clpyridine-5-carboxylate
(Compound 57e)
[0550] To a THF (1.1 mL) solution of Compound 57d (115 mg, 0.17 mmol) obtained in Step 57-3
was added at room temperature methylsulfonic acid (0.011 mL, 0.17 mmol), then the
mixture was stirred at 60°C for 90 min. Potassium phosphate (36.5 mg, 0.172 mmol),
water (0.45 mL) and (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012 mL,
0.052 mmol) were added to the reaction mixture, and the resulting mixture was stirred
for 1 h. Then, after the reaction mixture was diluted with dichloromethane, it was
washed with water. The organic layer was dried using magnesium sulfate, and the solvent
was removed by evaporation under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate/hexane=1:2 to 1:1) to obtain the titled Compound
57e (48.5 mg, yield 43%).
[0551] LC/MS mass spectrometry: m/z 660 ([M+H]
+).
[0552] LC/MS retention time: 1.04 min. (Analysis Condition: SQD-FA05-1).
<Step 57-5>
tert-Butyl (4S)-3-[3-[4-[acetyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 57f)
[0553] To a THF (0.22 mL) solution of Compound 57e (16.1 mg, 0.024 mmol) obtained in Step
57-4 was added at -26°C, a 1.7M potassium pentoxide toluene solution (0.024 mL, 0.041
mmol), and the mixture was stirred at -30°C for 3 min. Acetic anhydride (8 µL, 0.085
mmol) was added to the reaction mixture at -30°C, and the mixture was stirred at a
temperature of -30°C to -25°C for 5 min. and at a temperature of -25°C to room temperature
for 3 min. After water (0.5 mL) was added to the reaction mixture, the mixture was
diluted using ethyl acetate, and more water was added and extraction was performed
using ethyl acetate. The organic layer was dried using magnesium sulfate, and the
solvent was removed by distillation under reduced pressure, then the resulting product
was purified by silica gel column chromatography (ethyl acetate/hexane=1:3 to 2:3)
to obtain the titled Compound 57f (9.2 mg, yield 54%).
[0554] LC/MS mass spectrometry: m/z 701 ([M+H]
+).
[0555] LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA05-1).
<Step 57-6>
N-14-13-r(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]acetamide
2,2,2-trifluoroacetate (Compound 57g)
[0556] To a dichloromethane (0.097 mL) solution of Compound 57f (8.5 mg, 0.012 mmol) obtained
in Step 57-5 was added TFA (0.019 mL) at room temperature, and the resulting mixture
was stirred at room temperature for 3 h. After the solvent in the reaction mixture
was removed by evaporation under reduced pressure, toluene was added and the solvent
was removed by evaporation, and hexane-dichloromethane was added and the solvent was
removed by evaporation to obtain the titled Compound 57g (9.4 mg) as a crude product.
[0557] LC/MS mass spectrometry: m/z 501 ([M+H]
+).
[0558] LC/MS retention time: 0.49 min. (Analysis Condition: SQD-FA05-1).
<Step 57-7>
tert-Butyl (4S)-3-r3-(4-acetamidecuban-1-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 57h)
[0559] The titled compound was synthesized from Compound 57g obtained in Step 57-6 by performing
an operation similar to Step 51-1 of Example 51 using an appropriate reagent.
[0560] LC/MS mass spectrometry: m/z 602 ([M+H]
+).
[0561] LC/MS retention time: 0.85 min. (Analysis Condition: SQD-FA05-1).
<Step 57-8>
tert-Butyl (4S)-3-[3-[4-[acetyl(2-methoxyethyl)amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 57i)
[0562] The titled compound was synthesized from Compound 57h obtained in Step 57-7 by performing
an operation similar to Step 57-5 of Example 57 using an appropriate reagent.
[0563] LC/MS mass spectrometry: m/z 660 ([M+H]
+).
[0564] LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).
<Step 57-9>
N-14-13-r(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolor[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]cuban-1-yl]-N-(2-methoxyethyl)acetamide,
hydrochloride (Compound 57j)
[0565] The titled compound was synthesized from Compound 57i obtained in Step 57-8 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0566] LC/MS mass spectrometry: m/z 560 ([M+H]
+).
[0567] LC/MS retention time: 0.53 min. (Analysis Condition: SQD-FA05-1).
[0568] Compound 58e used in the synthesis of Example Compound 58 was synthesized as follows.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0084)
<Step 58-1>
tert-Butyl 3-amino-2- (4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 58a)
[0569] The titled compound was synthesized from Compound 1b obtained in Step 1-1 and Compound
46a obtained in Step 46-1 by performing an operation similar to Step 1-2 of Example
1 using an appropriate reagent.
[0570] LC/MS mass spectrometry: m/z 347 ([M+H]
+).
[0571] LC/MS retention time: 0.98 min. (Analysis Condition: SMD-FA05-3).
<Step 58-2>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 58b)
[0572] The titled compound was synthesized from Compound 58a obtained in Step 58-1 by performing
an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
[0573] LC/MS mass spectrometry: m/z 478 ([M+H]
+).
[0574] LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-3).
<Step 58-3>
tert-Butyl 2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 58c)
[0575] The titled compound was synthesized from Compound 58b obtained in Step 58-2 by performing
an operation similar to Step 11-7 of Example 11 using an appropriate reagent.
[0576] LC/MS mass spectrometry: m/z 414 ([M+H]
+).
[0577] LC/MS retention time: 0.72 min. (Analysis Condition: SQD-FA05-1).
<Step 58-4>
tert-Butyl 2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolol4,3-c]pyridine-5-carboxylate
(Compound 58d)
[0578] The titled compound was synthesized from Compound 58c obtained in Step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole
(Compound 56a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0579] LC/MS mass spectrometry: m/z 588 ([M+H]
+).
[0580] LC/MS retention time: 0.88 min. (Analysis Condition: SQD-FA05-1).
<Step 58-5>
1-[2-(4-Fluoro-3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one
hydrochloride (Compound 58e)
[0581] The titled compound was synthesized from Compound 58d obtained in Step 58-4 by performing
an operation similar to Step 11-9 of Example 11 using an appropriate reagent.
[0582] LC/MS mass spectrometry: m/z 488 ([M+H]
+).
[0583] LC/MS retention time: 0.50 min. (Analysis Condition: SQD-FA05-1).
[0584] Compound 60c used in the synthesis of Example Compound 60 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0085)
<Step 60-1>
tert-Butyl 2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 60a)
[0585] The titled compound was synthesized from Compound 1g obtained in Step 1-4 by performing
an operation similar to Step 51-1 of Example 51 using an appropriate reagent.
[0586] LC/MS mass spectrometry: m/z 410 ([M+H]
+).
[0587] LC/MS retention time: 0.77 min. (Analysis Condition: SQD-FA05-1).
<Step 60-2>
tert-Butyl 2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazol
o [4,3 -cl pyri dine-5 -carb oxyl ate (Compound 60b)
[0588] The titled compound was synthesized from Compound 60a obtained in Step 60-1 and 5-bromo-1-methylindazole
(Compound 1q) by performing an operation similar to Step 1-11 of Example 1 using an
appropriate reagent.
[0589] LC/MS mass spectrometry: m/z 540 ([M+H]
+).
[0590] LC/MS retention time: 1.24 min. (Analysis Condition: SMD-FA05-3).
<Step 60-3>
1-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-clpyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 60c)
[0591] The titled compound was synthesized from Compound 60b obtained in Step 60-2 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0592] LC/MS mass spectrometry: m/z 440 ([M+H]
+).
[0593] LC/MS retention time: 0.74 min. (Analysis Condition: SMD-FA05-2).
[0594] Compound 61b used in the synthesis of Example Compound 61 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0086)
<Step 61-1>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yI1-6,
7-dihydro-4H-pyrazolor 43-c 1pyridine-5-carboxylate (Compound 61a)
[0595] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-1-methylindazole
(Compound 1q) by performing an operation similar to Step 1-11 of Example 1 using an
appropriate reagent.
[0596] LC/MS mass spectrometry: m/z 572 ([M+H]
+).
[0597] LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 61-2>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-
(1-methylindazol-5-yl)imidazol-2-one hydrochloride (Compound 61b)
[0598] The titled compound was synthesized from Compound 61a obtained in Step 61-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0599] LC/MS mass spectrometry: m/z 472 ([M+H]
+).
[0600] LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA05-1).
[0601] Compound 62b used in the synthesis of Example Compound 62 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0087)
<Step 62-1>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 62a)
[0602] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-1-
(2-methoxyethyl)indazole (Compound 56a) by performing an operation similar to Step
1-11 of Example 1 using an appropriate reagent.
[0603] LC/MS mass spectrometry: m/z 616 ([M+H]
+).
[0604] LC/MS retention time: 1.29 min. (Analysis Condition: SMD-FA05-1).
<Step 62-2>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one
hydrochloride (Compound 62b)
[0605] The titled compound was synthesized from Compound 62a obtained in Step 62-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0606] LC/MS mass spectrometry: m/z 516 ([M+H]
+).
[0607] LC/MS retention time: 0.76 min. (Analysis Condition: SMD-FA05-1).
[0608] Compound 63g used in the synthesis of Example Compound 63 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0088)
<Step 63-1>
5-Bromo-7-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound 63b)
[0609] The titled compound was synthesized from 5-bromo-7-fluoro-1H-indole-2-carboxylic
acid (Compound 63a) by performing an operation similar to Step 1-10 of Example 1 using
an appropriate reagent.
<Step 63-2>
5-Bromo-1-(cyanomethyl)-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (Compound 63c)
[0610] The titled compound was synthesized from Compound 63b obtained in Step 63-1 by performing
an operation similar to Step 9-1 of Example 9 using an appropriate reagent.
[0611] LC/MS mass spectrometry: m/z 386 ([M+H]
+).
[0612] LC/MS retention time: 3.17 min. (Analysis Condition: SMD-FA10-long).
<Step 63-3>
5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-N-phenylindole-2-carboxamide
(Compound 63d)
[0613] The titled compound was synthesized from Compound 63c obtained in Step 63-2 by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0614] LC/MS mass spectrometry: m/z 426 ([M+H]
+).
[0615] LC/MS retention time: 1.36 min. (Analysis Condition: SMD-FA05-1).
[0616] 1H-NMR (300 MHz, CDCl
3) δ: 7.75 (1H, s), 7.43-7.30 (6H, m), 6.08 (1H, brs), 3.44 (3H, s), 2.11-1.69 (3H,
m), 1.40-1.35 (3H, m).
<Step 63-4>
1-1(1S,2S)-1-Cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide
(Compound 63e)
[0617] The titled compound was synthesized from Compound 63d obtained in Step 63-3 and (tetrahydro-2H-
pyran-4-yl)zinc (II) iodide (Compound 8a) by performing an operation similar to Step
8-1 of Example 8 using an appropriate reagent.
[0618] LC/MS mass spectrometry: m/z 432 ([M+H]
+).
[0619] LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA05-1).
<Step 63-5>
7-Fluoro-N-methyl-1-r(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropy]-5-(oxan-4-yl)-N-phenylindole-2-carboxamide
(Compound 63f)
[0620] The titled compound was synthesized from Compound 63e obtained in Step 63-4 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0621] LC/MS mass spectrometry: m/z 491 ([M+H]
+).
[0622] LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-01).
<Step 63-6>
7-Fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2-carboxylic
acid (Compound 63g)
[0623] The titled compound was synthesized from Compound 63f obtained in Step 63-5 by performing
an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
[0624] LC/MS mass spectrometry: m/z 402 ([M+H]
+).
[0625] LC/MS retention time: 0.97 min. (Analysis Condition: SMD-FA05-1). Compound 64b used
in the synthesis of Example Compound 64 was synthesized by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0089)
<Step 64-1>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 64a)
[0626] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and Compound
8f obtained in Step 8-4 by performing an operation similar to Step 1-11 of Example
1 using an appropriate reagent.
[0627] LC/MS mass spectrometry: m/z 628 ([M+H]
+).
[0628] LC/MS retention time: 1.32 min. (Analysis Condition: SMD-FA05-1).
<Step 64-2>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-2-one
hydrochloride (Compound 64b)
[0629] The titled compound was synthesized from Compound 64a obtained in Step 64-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0630] LC/MS mass spectrometry: m/z 528 ([M+H]
+).
[0631] LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1). Compound 65c used
in the synthesis of Example Compound 65 was synthesized by the following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0090)
<Step 65-1>
tert-Butyl (4S)-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 65b)
[0632] The titled compound was synthesized from Compound 42e obtained in Step 42-4 and 5-bromo-4-fluoro-1-methylindazole
(Compound 65a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0633] LC/MS mass spectrometry: m/z 606 ([M+H]
+).
[0634] LC/MS retention time: 1.38 min. (Analysis Condition: SMD-FA05-1).
<Step 65-2>
1-[(4S)-2-(4-Chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 65c)
[0635] The titled compound was synthesized from Compound 65b obtained in Step 65-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0636] LC/MS mass spectrometry: m/z 506 ([M+H]
+).
[0637] LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA05-1).
[0638] Compound 67b used in the synthesis of Example Compound 67 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0091)
<Step 67-1>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 67a)
[0639] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-4-fluoro-1-methylindazole
(Compound 65a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0640] LC/MS mass spectrometry: m/z 590 ([M+H]
+).
[0641] LC/MS retention time: 1.31 min. (Analysis Condition: SMD-FA05-1).
<Step 67-2>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-l-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 67b)
[0642] The titled compound was synthesized from Compound 67a obtained in Step 67-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0643] LC/MS mass spectrometry: m/z 490 ([M+H]
+).
[0644] LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).
[0645] Compound 68c used in the synthesis of Example Compound 68 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0092)
<Step 68-1>
tert-Butyl (4S)-3-[3-(4-chloro-l-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 68b)
[0646] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-4-chloro-1-methylindazole
(Compound 68a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0647] LC/MS mass spectrometry: m/z 606 ([M+H]
+).
[0648] LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).
<Step 68-2>
1-(4-Chloro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one
hydrochloride (Compound 68c)
[0649] The titled compound was synthesized from Compound 68b obtained in Step 68-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0650] LC/MS mass spectrometry: m/z 506 ([M+H]
+).
[0651] LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).
[0652] Compound 69b used in the synthesis of Example Compound 69 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0093)
<Step 69-1>
tert-Butyl (4S)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 69a)
[0653] The titled compound was synthesized from Compound 46d obtained in Step 46-3 and 5-bromo-4-fluoro-1-methylindazole
(Compound 65a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0654] LC/MS mass spectrometry: m/z 576 ([M+H]
+).
[0655] LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).
<Step 69-2>
1-(4-Fluoro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one
hydrochloride (Compound 69b)
[0656] The titled compound was synthesized from Compound 69a obtained in Step 69-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0657] LC/MS mass spectrometry: m/z 476 ([M+H]
+).
[0658] LC/MS retention time: 0.77 min. (Analysis Condition: SMD-FA05-1).
[0659] Compound 70c used in the synthesis of Example Compound 70 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0094)
<Step 70-1>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 70b)
[0660] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and 5-bromo-6-fluoro-1-methylindazole
(Compound 70a) by performing an operation similar to Step 1-11 of Example 1 using
an appropriate reagent.
[0661] LC/MS mass spectrometry: m/z 590 ([M+H]
+).
[0662] LC/MS retention time: 1.28 min. (Analysis Condition: SMD-FA05-1).
<Step 70-2>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(6-fluoro-1-methylindazol-5-yl)imidazol-2-one
hydrochloride (Compound 70c)
[0663] The titled compound was synthesized from Compound 70b obtained in Step 70-1 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0664] LC/MS mass spectrometry: m/z 490 ([M+H]
+).
[0665] LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).
[0666] Compound 71b used in the synthesis of Example Compound 71 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0095)
<Step 71-1>
5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (Compound 71b)
[0667] The titled compound was synthesized from 5-bromo-6-fluoro-1H-indazole (Compound 71a)
by performing an operation similar to Step 8-4 of Example 8 using an appropriate reagent.
[0668] LC/MS mass spectrometry: m/z 273 ([M+H]
+).
[0669] LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-1).
<Step 71-2>
tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
(Compound 71c)
[0670] The titled compound was synthesized from Compound 11k obtained in Step 11-7 and Compound
71b obtained in Step 71-1 by performing an operation similar to Step 1-11 of Example
1 using an appropriate reagent.
[0671] LC/MS mass spectrometry: m/z 634 ([M+H]
+).
[0672] LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 71-3>
1-[(4S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[6-fluoro-l-(2-methoxyethyl)indazol-5-yl]imidazol-2-one
hydrochloride (Compound 71d)
[0673] The titled compound was synthesized from Compound 71c obtained in Step 71-2 by performing
an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
[0674] LC/MS mass spectrometry: m/z 534 ([M+H]
+).
[0675] LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).
<Example 73> Synthesis of 3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 73)
<Step 73-1>
[0676]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0096)
[0677] To a DMF (1.5 mL) solution of a racemic form (Compound 73a, 29.6 mg, 0.058 mmol)
synthesized by a method similar to the compound obtained in Step 61-2 and Compound
1o (26.8 mg, 0.064 mmol) obtained in Step 1-9 were added HATU (26.6 mg, 0.070 mmol)
and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol), and the mixture was stirred at
room temperature for an hour. The reaction solution was diluted by ethyl acetate,
and washed with distilled water. The organic layer was concentrated under reduced
pressure to obtain a residue which is a mixture of stereoisomers. The stereoisomers
were separated by reversed-phase HPLC to obtain Entity A (14.5 mg, yield 29%) and
Entity B (15.5 mg, yield 31%), which is a white, solid, titled Compound 73.
Separation Condition
[0678]
Column: YMC Actus ODS-A, 20×100 mm, 5 µm
Solvent: 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution=40/60
(homogenous system)
Flow rate: 20 mL/min., room temperature
Entity A
LC/MS mass spectrometry: m/z 872 ([M+H]+).
LC/MS retention time: 0.99 min. (Analysis Condition: SMD-FA05-3).
Entity B (Compound 73)
LC/MS mass spectrometry: m/z 872 ([M+H]+).
LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-3).
<Example 74> Synthesis of 3-[(1S,2S)-1-[6-Fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 74)
[0679]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0097)
<Step 74-1>
5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (Compound 74b)
[0680] The titled compound was synthesized from 5-bromo-6-fluoro-1H-indole-2-carboxylic
acid (Compound 74a) by performing an operation similar to Step 1-10 of Example 1 using
an appropriate reagent.
[0681] LC/MS mass spectrometry: m/z 347 ([M+H]
+).
[0682] LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA05-4).
<Step 74-2>
5-Bromo-1- (cyanomethyl)-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (Compound
74c)
[0683] The titled compound was synthesized from Compound 74b obtained in Step 74-1 by performing
an operation similar to Step 9-1 of Example 9 using an appropriate reagent.
[0684] LC/MS mass spectrometry: m/z 386 ([M+H]
+).
[0685] LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA50-4).
<Step 74-3>
5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-6-fluoro-N-methyl-N-phenylindole-2-carboxamide
(Compound 74d)
[0686] The titled compound was synthesized from Compound 74c obtained in Step 74-2 and (4R)-4-methyl-1,3,2-dioxathiolane
2,2-dioxide (Compound 1k) by performing an operation similar to Step 1-6 of Example
1 using an appropriate reagent.
[0687] LC/MS mass spectrometry: m/z 426 ([M+H]
+).
[0688] LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA10-5).
<Step 74-4>
5-Bromo-6-fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-phenylindole-2-carboxamide
(Compound 74e)
[0689] The titled compound was synthesized from Compound 74d obtained in Step 74-3 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0690] LC/MS mass spectrometry: m/z 485 ([M+H]
+).
[0691] LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-1).
<Step 74-5>
5-Bromo-6-fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic
acid (Compound 74f)
[0692] The titled compound was synthesized from Compound 74e obtained in Step 74-4 by performing
an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
[0693] LC/MS mass spectrometry: m/z 396 ([M+H]
+).
[0694] LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).
<Step 74-6>
3-[(1S,2S)-1-[5-Bromo-6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 74g)
[0695] The titled compound was synthesized from Compound 74f obtained in Step 74-5 and Compound
61b obtained in Step 61-2 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0696] LC/MS mass spectrometry: m/z 849 ([M+H]
+).
[0697] LC/MS retention time: 1.42 min. (Analysis Condition: SMD-FA05-1).
<Step 74-7>
3-[(1S,2S)-1-[6-Fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-
(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 74)
[0698] The titled compound was synthesized by performing an operation similar to Step 6-5
of Example 6 using Compound 74g obtained in Step 74-6 and 4-iodo-2-methoxy3-methylpyridine
(Compound 6g), and an appropriate reagent.
[0699] LC/MS mass spectrometry: m/z 892 ([M+H]
+).
[0700] LC/MS retention time: 1.48 min. (Analysis Condition: SMD-TFA05-1).
<Examples 75-77>
[0702] Compound 75b used in the synthesis of Example Compound 75 was synthesized by the
following process.
<Step 75-1>
Iodo(6-oxaspirol4.51decan-9-yl) zinc (Compound 75b)
[0703]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0101)
[0704] The titled compound was synthesized from 9-iodo-6-oxaspiro[4.5]decane (Compound 75a)
by performing an operation similar to Step 41-1 of Example 41 using an appropriate
reagent.
[0705] The compound was directly put to use in the next step.
[0706] Compound 76a used in the synthesis of Example Compound 76 was synthesized by the
following process.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0102)
<Step 76-1>
3-[(1S,2S)-1-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 76a)
[0707] The titled compound was synthesized from Compound 56b obtained in Step 56-1 and Compound
6f obtained in Step 6-4 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0708] LC/MS mass spectrometry: m/z 861 ([M+H]
+).
[0709] LC/MS retention time: 1.45 min. (Analysis Condition: SMD-FA05-2).
<Example 77>
[0710]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0103)
<Step 77-1>
2-Ethyl-4-iodooxane (Compound 77b)
[0711] To an acetic acid (2.48 mL) solution of but-3-en-1-ol (0.588 mL, 6.93 mmol) was sequentially
added propionaldehyde (0.650 mL, 9.01 mmol) and lithium iodide (2.78 g, 20.8 mmol),
and the mixture was stirred at 60°C for 1 h. Water was added to the reaction mixture,
and extraction was performed using dichloromethane. The organic layer was washed with
10% sodium thiosulfate aqueous solution and saturated sodium acid carbonate aqueous
solution, then dried with magnesium sulfate. After filtration, the filtrate was concentrated
under reduced pressure (lower limit being 150 hpa), and the residue was purified by
silica gel chromatography (ethyl acetate/hexane=0: 1 to 1:9) to obtain the titled
Compound 77b as a pale yellow oil-like diastereomer mixture (1.12 g, yield 67%, syn:anti=1.00:0.45).
[0712] 1H-NMR (400 MHz,CDCl
3):
syn δ: 4.31-4.23 (1H, m), 3.90-3.82 (1H, m), 3.44-3.37 (1H, m), 3.21-3.15 (1H, m),
2.37-1.38 (6H, m), 0.92 (3H, t, J=7.4 Hz).
anti δ: 4.87-4.84 (1H, m), 3.90-3.82 (2H, m), 3.70-3.64 (1H, m), 2.37-1.38 (6H, m),
0.94 (3H, t, J=7.6 Hz).
<Step 77-2>
(2-Ethyloxan-4-yl)-iodozinc (Compound 77c)
[0713] To a DMA (0.25 mL) solution of zinc (102 mg, 1.56 mmol) was slowly added dropwise
a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane
(0.012 mL, 0.137 mmol) under a nitrogen atmosphere while maintaining a temperature
of 65°C or lower, and the mixture was stirred at room temperature for 15 min. Then,
the DMA (0.625 mL) solution of Compound 77b (300 mg, 1.25 mmol) obtained in Step 77-1
was added dropwise slowly into the mixture while maintaining a temperature of 65°C
or lower, and the mixture was stirred under a nitrogen atmosphere at room temperature
for 30 min. to obtain a DMA solution (0.86M) of a diastereomer mixture of the titled
Compound 77c.
<Step 77-3>
3-[(1S,2S)-1-[5-(2-Ethyloxan-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 77)
[0714] To a DMA (0.163 mL) solution of Compound 51d (40.0 mg, 0.049 mmol) obtained in Step
51-4 were added palladium(II) acetate (2.20 mg, 0.00978mmol), and 2- (2-dicyclohexylphosphanylphenyl)-1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine
(8.54 mg, 0.020 mmol), and the mixture was de-aerated under reduced pressure, then
nitrogen was introduced in the vessel and the mixture was stirred at room temperature
for 5 min. Then, a DMA (0.86 M, 0.398 mL, 0.342 mmol) solution of Compound 77c obtained
in Step 77-2 was added and the mixture was stirred at room temperature for 1.5 h.
Formic acid was added to the reaction mixture, and the reaction mixture was purified
by reversed-phase silica gel chromatography (acetonitrile/water, 0.1% formic acid)
to obtain the syn-type diastereomer mixture. The syn-type diastereomer mixture was
separated into stereoisomers by the reversed-phase HPLC to obtain a white, amorphous
Entity A (17.4 mg, yield 41%) and a white, amorphous Entity B (14.9 mg, yield 37%),
which is the titled Compound 77.
Separation Condition
[0715]
Column: CHIRALCEL OD-RH 5 µm, 4.6 mm×150 mm (Daicel)
Solvent: 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution=20/80
(homogenous system)
Flow rate: 1.0 mL/min., room temperature
Entity A
LC/MS mass spectrometry: m/z 851 ([M+H]+).
HPLC retention time: 4.99 min. (Separation condition).
LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).
Entity B (Compound 77)
LC/MS mass spectrometry: m/z 851 ([M+H]+).
HPLC retention time: 6.64 min. (Separation condition).
LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).
<Example 78> Synthesis of 3-[(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 78)
[0716]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0104)
<Step 78-1>
2-[5-Bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]acetonitrile
(Compound 78a)
[0717] The titled compound was synthesized from Compound 51c obtained in Step 51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic
acid (Compound 6a) by performing an operation similar to Step 1-10 of Example 1 using
an appropriate reagent.
[0718] LC/MS mass spectrometry: m/z 718 ([M+H]
+).
[0719] LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 78-2>
2-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]acetonitrile
(Compound 78b)
[0720] The titled compound was synthesized from Compound 78a obtained in Step 78-1 and (tetrahydro-2H-pyran-4-yl)zinc
(II) iodide (Compound 8a) by performing an operation similar to Step 8-1 of Example
8 using an appropriate reagent.
[0721] LC/MS mass spectrometry: m/z 724 ([M+H]
+).
[0722] LC/MS retention time: 1.21 min. (Analysis Condition: SMD-FA05-1).
<Step 78-3>
(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropane-1-carbonitrile
(Compound 78d)
[0723] The titled compound was synthesized from Compound 78b obtained in Step 78-2 by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0724] LC/MS mass spectrometry: m/z 778 ([M+H]
+).
[0725] LC/MS retention time: 1.27 min. (Analysis Condition: SMD-FA05-RP).
<Step 78-4>
3-[(1S,2S)-2-Ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 78)
[0726] The titled compound was synthesized from Compound 78d obtained in Step 78-2 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0727] LC/MS mass spectrometry: m/z 837 ([M+H]
+).
[0728] LC/MS retention time: 1.39 min. (Analysis Condition: SMD-TFA05-2).
<Example 79> Synthesis of 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 79)
[0729]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0105)
<Step 79-1>
5-Bromo-1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-phenylindole-2-carboxamide
(Compound 79b)
[0730] The titled compound was synthesized from Compound 6c obtained in Step 6-1 and (4R)-4-
(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide (Compound 79a) by performing
an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
[0731] LC/MS mass spectrometry: m/z 514 ([M+H]
+).
[0732] LC/MS retention time: 1.48 min. (Analysis Condition: SMD-FA05-1).
<Step 79-2>
1-[(1S,2S)-1-Cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-5-(oxan-4-yl)-N-phenylindole-2-carboxamide
(Compound 79c)
[0733] The titled compound was synthesized from Compound 79b obtained in Step 79-1 and (tetrahydro-2H-pyran-4-yl)zinc
(II) iodide (Compound 8a) by performing an operation similar to Step 8-1 of Example
8 using an appropriate reagent.
[0734] LC/MS mass spectrometry: m/z 520 ([M+H]
+).
[0735] LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
<Step 79-3>
N-Methyl-5-(oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]-N-phenylindole-2-carboxamide
(Compound 79d)
[0736] The titled compound was synthesized from Compound 79c obtained in Step 79-2 by performing
an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
[0737] LC/MS mass spectrometry: m/z 579 ([M+H]
+).
[0738] LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
<Step 79-4>
5-(Oxan-4-yl)-1-[(1S,2S)-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-(phenylmethoxymethyl)cyclopropyl]indole-2-carboxylic
acid (Compound 79e)
[0739] The titled compound was synthesized from Compound 79d obtained in Step 79-3 by performing
an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
[0740] LC/MS mass spectrometry: m/z 490 ([M+H]
+).
[0741] LC/MS retention time: 1.12 min. (Analysis Condition: SMD-FA05-1).
<Step 79-5>
3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(phenylmethoxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 79f)
[0742] The titled compound was synthesized from Compound 79e obtained in Step 79-4 and Compound
51c obtained in Step 51-3 by performing an operation similar to Step 1-10 of Example
1 using an appropriate reagent.
[0743] LC/MS mass spectrometry: m/z 929 ([M+H]
+).
[0744] LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).
<Step 79-6>
3-[(1S,2S)-1-[2-[2-(4-Fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-(hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 79)
[0745] The dichloromethane (0.762 mL) solution of Compound 79f (35.4 mg, 0.0381mmol) obtained
in Step 79-5 was cooled to 0°C, and a hexane solution (0.191 mL, 0.191 mmol) of 1M
boron trichloride was slowly added. The reaction solution was warmed to room temperature
and stirred for 105 min., and then saturated sodium acid carbonate solution was added
to the reaction solution and the water layer was subjected to extraction using dichloromethane.
The organic layer was washed with brine and dried with sodium sulfate. After filtration,
the filtrate was concentrated under reduced pressure and the residue was purified
by reversed-phase column chromatography (acetonitrile/water, 0.1% formic acid) to
obtain the titled compound (18.5 mg, yield 50%).
[0746] LC/MS mass spectrometry: m/z 839 ([M+H]
+).
[0747] LC/MS retention time: 1.20 min. (Analysis Condition: SMD-TFA05-1).
<Example 80> Synthesis of 3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-y]l-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 80)
[0748]
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0106)
<Step 80-1>
Ethyl (E)-3-[[(2S)-1-Cyanopropan-2-yl]amino]but-2-enoate (Compound 80c)
[0749] To an acetonitrile (50 mL) solution of (3 S)-3-aminobutanenitrile (Compound 80b,
7.0 g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) was added ethyl 3-oxobutanoate (Compound
80a, 13 g, 99.9 mmol), and the mixture was stirred at room temperature for 4 h. The
reaction solution was concentrated under reduced pressure and the solvent was removed
by evaporation, and then the residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate=1:0 to 3:2) to obtain the titled Compound 80c (9.5
g, yield 58%) as a yellow oil-like material.
[0750] LC/MS mass spectrometry: m/z 197 ([M+H]
+).
[0751] LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA10-1).
<Step 80-2>
Ethyl 3-[[(2S)-1-Cyanopropan-2-yl]amino]butanoate (Compound 80d)
[0752] To a dichloromethane (200 mL) solution of Compound 80c (10g, 51.0 mmol) obtained
in Step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol) was added acetic
acid (3 mL), and the mixture was stirred at room temperature for 16 h. Water and acetic
acid were added to the reaction solution, and the pH was adjusted to 5, and then the
water layer was subjected to extraction using ethyl acetate. The organic layer was
washed with brine and dried using sodium sulfate. After filtration, the filtrate was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate=1:0 to 1:4) to obtain the titled Compound
80d (5.5 g, yield 54%) as a yellow oil-like material.
[0753] LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA10-4).
<Step 80-3>
(6S)-1-Formyl-4-hydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridine-5-carbonitrile (Compound
80e)
[0754] A toluene (5 mL) solution of Compound 80d (1.0 g, 5.04 mmol) obtained in Step 80-2
was added dropwise slowly at 80°C to a toluene (10 mL) solution of potassium tert-butoxide
(680 mg, 6.06 mmol). After the solution was stirred at 80°C for 1h., the solution
was cooled to room temperature to obtain a toluene solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile.
[0755] A toluene (5 mL) solution of acetic anhydride (12.1 g, 118 mmol) was added dropwise
slowly into formic acid (7.26 g) at 0°C and stirred at 0°C for 30 min., and then the
toluene solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile
that had been prepared was added dropwise slowly. After the reaction solution was
stirred at 110°C for 16 h., it was cooled to room temperature and concentrated under
reduced pressure to remove the solvent by evaporation, and a mixture (1.3 g) containing
the titled Compound 80e was obtained as an oil-like material.
<Step 80-4>
(4S)-3-Amino-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde
(Compound 80f)
[0756] The ethanol (30 mL) solution of Compound 80e (1.30 g, 7.21 mmol) obtained in Step
80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 2c, 690 mg,
3.62 mmol) was heated to 75°C and was stirred for 16 h. The reaction solution was
cooled to room temperature and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (dichloromethane /methanol=1:0 to 9:1),
and the titled Compound 80f (2 steps from Step 80-3, 800 mg, yield 35%) was obtained
as a yellow solid.
[0757] LC/MS mass spectrometry: m/z 317 ([M+H]
+).
[0758] LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA10-3).
<Step 80-5>
1-(2,2-Dimethoxyethyl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-formyl-4,6-dimethyl-6,7-dihydro-4H-pyrazolol4,3-c1pyridin-3-yl1urea
(Compound 80g)
[0759] 2,2-Dimethoxyethane-1-amine (1.14 g, 10.8 mmol) was added at 0°C to a DMA (50 mL)
solution of N,N'-carbodiimidazole (1.63 g, 10.1 mmol), and the mixture was stirred
for 30 min. To the solution was added sequentially potassium tert-butoxide (5.62 g,
50.1 mmol) and Compound 80f (2.64 g, 8.34 mmol) obtained in Step 80-4. After the mixture
was stirred at room temperature for 6 h., water was added, and the water layer was
subjected to extraction using ethyl acetate. After the organic layer was washed with
brine, it was dried with sodium sulfate. After filtration, the filtrate was concentrated
under reduced pressure to obtain the titled Compound 80g (2.80 g, yield 75%) as a
brown oil-like material.
[0760] LC/MS mass spectrometry: m/z 448 ([M+H]
+).
[0761] LC/MS retention time: 0.84 min. (Analysis Condition: SMD-FA10-2).
<Step 80-6>
(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde
(Compound 80h)
[0762] A DMF (30 mL) solution of Compound 80g (2.50 g, 5.59 mmol) obtained in Step 80-5
and 4-methylbenzenesulfonic acid (1.06 g, 6.16 mmol) was heated to 80°C and stirred
for 2 h. After the solution was cooled to room temperature, water was added and the
water layer was subjected to extraction using ethyl acetate. The organic layer was
washed with brine, and dried with sodium sulfate. After filtration, the filtrate was
concentrated under reduced pressure. The obtained residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate=1:0 to 3:1), to obtain the diastereomer
mixture (480 mg) containing the titled compound (Compound 80h) as a white solid.
[0763] LC/MS mass spectrometry: m/z 384 ([M+H]
+).
[0764] LC/MS retention time: 1.64 min. (Analysis Condition: SMD-TFA05-6).
[0765] The diastereomer mixture (480 mg, 5.59 mmol) containing the titled compound (Compound
80h: (4S,6R)-2- (4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3- (2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbaldehyde)
was separated to stereoisomers by SFC to obtain Entity A (155 mg, yield 7.0%) which
is the titled Compound 80h and Entity B (270 mg, yield 12%).
SFC Separation condition
[0766]
Column: CHIRALPAK AD-H, 50×500 mm, 3 µm (Daicel)
Solvent: supercritical carbon dioxide/ethanol=70:30 (homogenous system)
Flow rate: 150 mL/min., 35°C
Detected wavelength: 254 nm
Entity A (Compound 80h)
SFC retention time: 4.07 min.
LC/MS mass spectrometry: m/z 384 ([M+H]+).
LC/MS retention time: 2.15 min. (Analysis Condition: SMD-FA1060-1).
[0767] 1H-NMR (300 MHz, DMSO-D
6) δ: 10.35 (1H, s), 8.24 (1H, s), 7.11 (2H, d, J=6.3 Hz), 6.60-6.58 (2H, m), 5.21-5.14
(1H, m), 4.46-4.21 (1H, m), 2.96-2.89 (1H, m), 2.74-2.68 (1H, m), 2.20 (6H, s), 1.27-1.13
(6H, m).
[0768] Note that the Compound 80h was determined to be the R-isomer from the result obtained
by 2D-NOESY that the steric configuration thereof is a cis configuration.
Entity B
[0769] SFC retention time: 5.60 min.
[0770] LC/MS mass spectrometry: m/z 384 ([M+H]
+).
[0771] LC/MS retention time: 2.16 min. (Analysis Condition: SMD-FA1060-1).
[0772] 1H-NMR (300 MHz, DMSO-D
6) δ: 10.35 (1H, s), 8.31 (1H, s), 7.08 (2H, d, J=6.3 Hz), 6.61-6.54 (2H, m), 5.39
(1H, q, J=6.9 Hz), 3.89-3.84 (1H, m), 2.90 (1H, dd, J=3.3, 15.6 Hz), 2.59-2.51 (1H,
m), 2.20 (6H, d, J=2.1 Hz), 1.55 (3H, d, J=6.6 Hz), 1.18 (3H, d, J=6.6 Hz).
<Step 80-7>
3-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one
(Compound 80i)
[0773] 5M Sodium hydroxide solution (0.261 mL) was added to an ethanol (1.0 mL) solution
of Compound 80h (100 mg, 0.261 mmol) obtained in Step 80-6, and the mixture was stirred
at 80°C for 10 h. After the mixture was cooled to room temperature and stirred for
60 h., saturated ammonium chloride aqueous solution was added and the mixture was
subjected to extraction using ethyl acetate to synthesize the titled Compound 80i
(79%, 73 mg) as a white solid.
[0774] LC/MS mass spectrometry: m/z 356 ([M+H]
+).
[0775] LC/MS retention time: 0.44 min. (Analysis Condition: SQD-FA05-2).
<Step 80-8>
1 -1 (4 S,6R)-2-(4-Fluoro-3,5 -dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazol-5-yl)imidazol-2-one
(Compound 80j)
[0776] Copper iodide (I) (4.02 mg, 0.021 mmol) was added at a room temperature to a N-methylpiperazine
(0.188 mL) suspension of Compound 80i (15 mg, 0.042 mmol) obtained in Step 80-7, 5-bromo-1-methylindazole
(Compound 1q, 10.7 mg, 0.051 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine
(6.00 mg, 0.042 mmol), and potassium carbonate (17.5 mg, 0.127 mmol), and the mixture
was stirred under a nitrogen atmosphere at 130°C for 90 min. The reaction mixture
was purified by reversed-phase silica gel chromatography (acetonitrile/water, 0.1%
formic acid) and concentrated under a reduced pressure. A saturated sodium acid carbonate
aqueous solution was added to the residue, and extraction was performed using ethyl
acetate, and then the organic layer was concentrated under reduced pressure to obtain
the titled Compound 80j (17.4 mg, yield 85%).
[0777] LC/MS mass spectrometry: m/z 486 ([M+H]
+).
[0778] LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-2).
<Step 80-9>
2-Trimethylsilylethoxymethyl 5-(oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4- (2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carboxylate
(Compound 80k)
[0779] To a DMF (2.6 mL) solution of Compound 8b (100 mg, 0.261 mmol) obtained in Step 8-1
was added 55 wt% sodium hydride (34.1 mg, 0.782 mmol) and 2-(trimethylsilyl)ethoxymethylchloride
(0.116 mL, 0.652 mmol), and the mixture was stirred under room temperature for 1 h.
A saturated ammonium chloride solution was added, and extraction was performed using
ethyl acetate. Then, the residue obtained after concentration was purified by normal
phase column chromatography (ethyl acetate/hexane) to obtain the titled Compound 80k
(147 mg, yield 88%) as a yellow gum-like material.
[0780] LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-2).
<Step 80-10>
5-(Oxan-4-yl)-1-r(1S,2S)-1-r5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carboxylic
acid (801)
[0781] To a dichloromethane (2.3 mL) solution of Compound 80k (147 mg, 0.228 mmol) obtained
in Step 80-9 was added a magnesium bromide/diethyl ether complex (295 mg, 1.14 mmol),
and the mixture was stirred at 0°C for 6.5 h. The mixture was warmed to room temperature
and stirred for 30 min., and then a saturated ammonium chloride aqueous solution was
added. Then, extraction was performed using ethyl acetate, and the resulting product
was concentrated, and then the residue was diluted with DMSO and water and purified
by reversed-phase chromatography (acetonitrile/water, 0.1% formic acid) to synthesize
the titled Compound 801 (60 mg, yield 51%).
[0782] LC/MS mass spectrometry: m/z 512 ([M-H]
-).
[0783] LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-2).
<Step 80-11>
5-(Oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-L2,4-oxadiazol-3-yl]-2-methylcyclopropyl]indole-2-carbonylchloride
(Compound 80m)
[0784] To an acetonitrile (0.36 mL) solution of Compound 801 (18 mg, 0.036 mmol) obtained
in Step 80-10 was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.0057 mg, 0.043
mmol), and the mixture was stirred at room temperature for 2 h., and then it was concentrated
to obtain a crude product of the titled Compound 80m. This compound was directly put
to use in the next step.
<Step 80-12>
3-[(1S2S)-2-[2-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4-(2-tnmethylsilylethoxymethyl)-1,2,4-oxadiazol-5-one
(Compound 80n)
[0785] Compound 80m obtained in Step 80-11 was dissolved in THF (0.717 mL), and Compound
80j (19.1 mg, 0.036 mmol) obtained in Step 80-8 and N,N-diisopropylethylamine (0.0188
mL, 0.108 mmol) were added to the solution, then the mixture was stirred at room temperature
for 22 h., and then methanol and formic acid were added. The mixture was concentrated,
and the residue was diluted with DMSO and water and purified by reversed-phase column
chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the titled Compound
80n (32 mg, yield 91%).
[0786] LC/MS mass spectrometry: m/z 982 ([M+H]
+).
[0787] LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA50-1).
<Step 80-13>
3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 80)
[0788] To a THF (0.326 mL) solution of Compound 80n (32 mg, 0.033 mmol) obtained in Step
80-12 was added acetic acid (0.0019 mL, 0.033 mmol) and a THF solution (0.065 mL,
0.065 mmol) of 1M tetrabutylammonium fluoride, and the mixture was stirred at 80°C
for 66 h. Acetic acid (0.0019 mL, 0.033 mmol) and a THF solution (0.065 mL, 0.065
mmol) of 1M tetrabutylammonium fluoride were added, and the mixture was stirred for
23.5 h. Further, a THF solution (0.065 mL, 0.065 mmol) of 1M tetrabutylammonium fluoride
was added, then the mixture was stirred for 7 h., and then formic acid was added.
After concentration, the mixture was diluted with DMSO and water and purified by reversed-phase
column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the titled
Compound 80 (18 mg, yield 65%).
[0789] LC/MS mass spectrometry: m/z 851 ([M+H]
+).
[0790] LC/MS retention time: 1.42 min. (Analysis Condition: SMD-TFA05-1).
<Example 160> Preparation of Monosodium Salt Hydrate Crystal of Compound 1
[0792] Acetonitrile (3.02 mL) was added to 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Compound 1, 1005.5 mg) obtained in Example 1 to dissolve the compound at room temperature.
5M Sodium hydroxide aqueous solution (0.495 mL) and seed crystals of sodium salt hydrate
of Compound 1 were added to the solution, and the mixture was stirred at room temperature
for 2 h. Tert-Butylmethyl ether (3.02 mL) was also added, and the mixture was stirred
at room temperature for 1 h., and then tert-butylmethyl ether (9.05 mL) was added
and the mixture was stirred at room temperature for 2 h. to obtain sodium salt hydrate
crystals of the titled compound (1007.0 mg) as powder crystals (Sample 160a). Note
that seed crystals were obtained by the following method.
[0793] DMSO (0.244 mL) and 2M sodium hydroxide aqueous solution (0.032 mL) were added to
Compound 1 (26.9 mg). This solution (0.030 mL) was freeze-dried at -20°C for 2 days.
Acetonitrile (0.015 mL) was added to the obtained, freeze-dried product, and the mixture
was stirred by shaking at room temperature for 2 days, and then tert-butylmethyl ether
(0.015 mL) was added, and the mixture was stirred by shaking at room temperature for
12 days to obtain sodium salt hydrate crystals of Compound 1 as powder crystals (Sample
160b).
<Example 161> Preparation of Crystal of Example Compound 66
[0794] 3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Example Compound 66, 400.3 mg) was suspended in ethanol (8.00 mL), to which seed
crystals of Example Compound 66 were added, and the mixture was stirred at 70°C for
5 min. After the suspension was stirred at 50°C for 1 h., it was stirred at room temperature
for 17 h. to obtain crystals (381.1 mg) of Example Compound 66 as powder crystals
(Sample 161a). Note that seed crystals were obtained by the following method.
[0795] Example Compound 66 (31.8 mg) was suspended in ethanol (0.636 mL), and stirred at
80°C. After the suspension was stirred at 40°C for 1 h., it was stirred at room temperature
for 22 h. to obtain crystals (24.2 mg) of Example Compound 66 as powder crystals (Sample
161b).
<Example 162> Preparation of Hemicalcium Salt Hydrate Crystal of Example Compound 67
[0796] Ethanol (5.60 mL) and 2M sodium hydroxide aqueous solution (0.75 mL) were added to
3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
(Example Compound 67, 1120 mg) and the compound was dissolved at room temperature.
1.26 M calcium acetate aqueous solution (0.68 mL), seed crystals of the calcium salt
hydrate of Example Compound 67 and water (0.68 mL) were added to the solution, and
the mixture was stirred at room temperature for 3 h. Further, water (1.2 mL) was added
and the mixture was stirred at room temperature for 1 h., and then water (2.3 mL)
was added and the mixture was stirred at room temperature for 1 h. to obtain calcium
salt hydrate crystals (973.0 mg) of Example Compound 67 as powder crystals (Sample
162a). Note that seed crystals were obtained by the following method.
[0797] Example Compound 67 (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06M calcium
methoxyethoxide (0.147 mL) was added. This solution (0.015 mL) was freeze-dried at
- 20°C for 2 days. Water-acetonitrile mixture (3:1, 0.015 mL) was added to the obtained,
freeze-dried product, and the mixture was stirred by shaking at room temperature for
7 days to obtain calcium salt hydrate crystals of Example Compound 67 as powder crystals
(Sample 162b).
<Example 163> Powder X-ray diffractometry
[0798] The sodium salt hydrate crystals (Samples 160a and 160b) of Compound 1 obtained in
Example 160, the crystals (Samples 161a and 161b) of Example Compound 66 obtained
in Example 161, the calcium salt hydrate crystals (Samples 162a and 162b) of Example
Compound 67 obtained in Example 162 were each subjected to powder X-ray diffractometry
by the following measurement method. The results are shown in Fig. 1 to Fig. 6.
Measurement Device: D8 Discover with GADDS CS diffractometer (Bruker AXS)
Anode: Cu
Voltage: 40 kV
Current: 40 mA
Scan Range: 5-25.3°
Step Width: 0.02°
<Example 164> Thermogravimetry/Differential thermal analysis
[0799] The sodium salt hydrate crystal of Compound 1 (Sample 160a) and the calcium salt
hydrate crystal of Example Compound 67 (Sample 162a) were each subjected to thermogravimetry/differential
thermal analysis by the following measurement method. The results are shown in Fig.
7 and Fig. 8. Note that Sample 160a was dehydrated by approximately 110°C and showed
no clear melting point. Also, Sample 162a was dehydrated by approximately 240°C and
showed no clear melting point.
[0800] Measurement Device: EXSTAR TG/DTA6200R (Seiko Instruments Inc. (Current Company Name:
Hitachi High-Tech Science Corporation))
Measurement Range: 30-350°C
Heat rate: 10°C/min.
Atmosphere: Nitrogen
<Example 165> Karl Fischer Water Measurement
[0801] The rate of water content in the sodium salt hydrate crystal of Compound 1 (Sample
160a) and the calcium salt hydrate crystal (Sample 162a) of Example Compound 67 were
measured using the coulometric Karl Fischer moisture meter (Metrohm, 756 KF Coulometer).
The result was 7.4% for Sample 160a and 6.2% for Sample 162a.
[0802] From the results of Example 164 and Example 165, it was confirmed that the waters
contained in the sodium salt hydrate crystal of Compound 1 and the calcium salt hydrate
crystal of Example Compound 67 were mainly crystalline water.
<Test Example 1> Measurement of in vitro cAMP Signal Activation of a Compound in
Human GLP1R
<Peptide>
[0803] The human GLP-1 (7-37) was obtained from PEPTIDE INSTITUTE, INC., and it was dissolved
in phosphate buffered saline to 200 µM, then stored in a freezer of -80°C.
<Cell Culture>
[0804] A human GLP1R stably-expressing cell line (hGLP1R-HEK293) was used in the experiment.
The cells were cultured in a Dulbecco's modified Eagle's medium (DMEM) containing
10% fetal bovine serum (Sigma-Aldrich), 100 units/mL penicillin G and 100 µg/mL streptomycin
sulfate (Gibco), and 500 µg/mL Geneticin (Gibco), under a moist atmosphere containing
5% CO
2, at 37°C.
<cAMP Assay>
[0805] hGLP1R-HEK293 was seeded in 96 well plates at 2.0×10
4 cells per well and cultured over night. The medium for culturing the cells was changed
to 50 µL of Medium A (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-methylxanthine)
the next day, and the cells were incubated at 37°C for 30 min. Then, 50 µL of Medium
B (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-methylxanthine) containing GLP-1
or the compound was added, and the cells were incubated at 37°C for an additional
30 min. Then, 100 µL of Assay lysis buffer (Applied Bioscience) was added, and the
cells were incubated at 37°C for 30 min. The cAMP concentration was quantified using
cAMP HiRange kit (Cisbio Bioassays).
<Calculation of EC50>
[0806] By setting the cAMP concentration when the human GLP-1 (7-37) was put into action
at a concentration of 1 nM to 100%, the cAMP concentration of each well was converted
to a reaction rate (%). By using a 4 parameter logistic regression analysis by XLfit
(ver 5.4.0.8), dose-response curves of the each Example Compound were created, and
the half maximal (50%) effective concentrations (EC
50) were calculated. The results are shown in Table 3.
![](https://data.epo.org/publication-server/image?imagePath=2024/11/DOC/EPNWB1/EP17853220NWB1/imgb0124)
<Test Example 2>:Insulin Secretion Promoting and Blood Glucose Lowering Effects
[0807] A solution of Example Compound 67 (solvent composition: PEG400 (10 vol%): propylene
glycol (10 vol%): 100 mM Glycine-NaOH buffer, pH 9.0 (80 vol%)) was intravenously
administered to a male cynomolgus monkey under anesthesia, for 40 min. continuously,
and a steady-state drug concentration in plasma of 0.94, 1.6 or 4.8 nmol/L was achieved.
Likewise, a solution of exenatide (solvent: Tween 0.05%/PBS(-)), which is a control
drug, was administered in the same manner, and a steady-state drug concentration in
plasma of 9.2 or 23.9 pmol/L was achieved. To the vehicle control group, the solvent
of Example Compound 67 was administered. Next, a 50% glucose solution (glucose administration
weight to the monkey: 0.5 g/kg) was intravenously administered and a blood sample
was collected every 5min or 10 min to measure the plasma insulin and glucose concentrations.
The area under the curve was calculated from the time course of each parameter after
the drug administration to evaluate the insulin secretion promoting effect and the
blood glucose lowering effect.
[0808] In the Example Compound 67 administered group, an increase in the area under the
curve of insulin (Fig. 9) and a decrease in the area under the curve of plasma glucose
(Fig. 10) in a dose-dependent manner, were observed at a steady-state concentration
in plasma of 0.94 to 4.8 nmol/L. A similar increase in the area under the curve of
insulin (Fig. 9) and decrease in the area under the curve of plasma glucose (Fig.
10) were observed in exenatide (control drug) administered group at a steady-state
plasma concentration of 9.2 to 23.9 pmol/L by the continuous intravenous administrations
[0809] Note that the 9.2 pmol/L (38.5 pg/mL) of exenatide was close to the lower limit of
the therapeutic concentration range (50-350 pg/mL) of exenatide in human diabetes
patients (Drug interview form, Byetta hypodermic injection 5 µg Pen 300, Byetta hypodermic
injection 10 µg Pen 300, September 2016 (revised ver. 9)). This result indicates that
Example Compound 67 exhibits an insulin secretion promoting effect and a blood glucose
lowering effect that are equivalent to exenatide, at a plasma concentration of 1.6
nmol/L or higher.
<Test Example 3>: Anorexigenic effects
[0810] Example Compound 67 was orally administered to male cynomolgus monkeys, for 5 consecutive
days, and its effects on the food intake for 90 min. from 3 h. after administration
were evaluated every day. Likewise, exenatide, which is a control drug, was subcutaneously
administered for 5 consecutive days, and its effect on the food intake for 90 min.
from 30 min. after administration were evaluated. To the vehicle control group, both
a solvent for oral administration of Example Compound 67 (DMSO (10 vol%): Cremophor
EL (10 vol%): PEG 400 (15 vol%): 100 mM Glycine-NaOH buffer, pH 10 (65 vol%), 1 mL/kg)
and a solvent for subcutaneous administration of exenatide (0.05 w/v% Tween/PBS(-),
0.1 mL/kg) were administered. At the same time, the solvent for subcutaneous administration
was additionally administered to the Example Compound 67 administered group (concentration
of administered drug, 0.05 or 0.1 mg/mL), and the solvent for oral administration
was additionally administered to the exenatide administered group (concentration of
administered drug, 3 or 6 µg/mL).
[0811] Example Compound 67 suppressed the food intake in a dosage dependent manner (Fig.
11A). The degree of suppression was almost equivalent to the control drug exenatide
(Fig. 11B). The plasma concentration of drug (mean value ± standard error) immediately
after measuring the food intake in each group were 8.0±1.0 nM (0.05 mg/kg group) and
16.3±2.3 nM (0.1 mg/kg group) for the Example Compound 67 administered group and 91±8.5
pM (0.3 µg/kg group) and 199±13.1 pM (0.6 µg/kg group) for the exenatide administered
group.
<Test Example 4> Pharmacokinetics of the Compounds
[0812] After oral administration (gavage administration using a gastric catheter) of a calcium
salt hydrate crystal (Sample 162a) suspension (Dosage: 0.05, 0.15, 0.45 and 1.35 mg/kg)
prepared from Example Compound 67 obtained in Example 162 to a male cynomolgus monkey
(n=2 for each dosage), blood was sequentially collected from the vein to obtain plasma.
The plasma concentrations of the drug were determined by liquid chromatography tandem-mass
spectrometry. The lower limit of quantification was 0.3 ng/mL. The time profile of
the plasma concentrations for the drug are shown in Fig. 12 and the time to reach
the maximum plasma concentration of the drug (T
max), the maximum plasma concentration of the drug (C
max) and the area under the plasma concentration - time curve of the drug up to 24 h.
after administration (AUC
0-24h) are shown in Table 4.
[0813] In all dosages, the plasma concentrations of the drug reached C
max at 2 h after oral administration, and then decreased in a similar time profile pattern.
The increase in the plasma exposure of drug at dosages of 0.05, 0.15, 0.45 and 1.35
mg/kg (Dosage ratio: 1:3:9:27) was nearly proportional to the increase in the dosage
(C
max ratio: 1.0:4.3:6.7:31, AUC
0-24h ratio: 1.0:5.7:8.8:44). It was shown that the present substance was dose-proportionally
absorbed in the intestinal tract and eliminated.
[Table 4]
Table 4. The Tmax, Cmax, and AUC0-24h after oral administration of the present substance to male cynomolgus monkeys |
Dose |
Tmax |
Cmax |
AUC0-24h |
(mg/kg) |
(Ratio) |
(h) |
(ng/mL) |
(Ratio) |
(ng·h/mL) |
(Ratio) |
0.05 |
1.0 |
2.0 |
4.78 |
1.0 |
23.7 |
1.0 |
0.15 |
3.0 |
2.0 |
20.7 |
4.3 |
135 |
5.7 |
0.45 |
9.0 |
2.0 |
32.0 |
6.7 |
208 |
8.8 |
1.35 |
27 |
2.0 |
148 |
31 |
1040 |
44 |